Anti-infective agents

ABSTRACT

The present invention provides HCV polymerase inhibiting compounds having the formula (I): 
     
       
         
         
             
             
         
       
     
     where R 1  is cyclobutyl—N(R a )-, n is 1, 2, 3 or 4, and at least one R 5  is R a SO 2 N(R j )alkyl-, In a non-limiting example, a compound of the present invention is N-[(3-{1-[(cyclobutyl)amino])-4-hydroxy -2-oxo-1,2-dihydro-quinolin-3-yl}-1,1-dioxo-1,4-dihydro-1λ 6 -thieno[2,3-e][1,2,4]thiadiazin-7-yl)methyl]methane-sulfonamide. The present invention also features compositions comprising the compounds of the present invention or pharmaceutically acceptable salts, stereoisomers or tautomers thereof, and methods of using the same to treat or prevent HCV infection.

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

This patent application claims priority to U.S. Provisional PatentApplication No. 60/831,853 (filed Jul. 19, 2006). The entire text ofthat application is incorporated by reference into this application.

TECHNICAL FIELD

The present invention features hepatitis C virus (HCV) polymeraseinhibiting compounds and compositions comprising the same. The presentinvention also features methods of using these compounds to inhibit HCVpolymerase and HCV viral replication. In addition, the present inventionfeature methods of using these compounds to treat or prevent HCVinfection. Processes for making these compounds, and syntheticintermediates employed in said processes, are also provided.

BACKGROUND OF THE INVENTION

Infection with hepatitis C virus (HCV) is a major cause of human liverdisease throughout the world. More than 85% of all infected individualsbecome chronically infected. Chronic HCV infection accounts for 30% ofall cirrhosis, end-stage liver disease, and liver cancer in the UnitedStates. The CDC estimates that the number of deaths due to HCV willincrease to 38,000 per year by the year 2010.

While initially therapy consisted of interferon alone, the combinationof interferon alpha-2b with ribavirin for either 24 or 48 weeks iscurrently the most efficacious approved therapy for the treatment ofchronic HCV infection. However, there are many adverse side effectsassociated with this therapy (flu-like symptoms, leukopenia,thrombocytopenia, and depression from interferon, as well as anemiainduced by ribavirin). Furthermore, this therapy is less effectiveagainst infections caused by HCV genotype 1 which constitutes about 75%of all HCV infections.

Based on the foregoing, there exists a significant need to identify newcompounds with the ability to inhibit HCV. The present inventionprovides novel anti-infective agents capable of inhibiting HCVpolymerase.

SUMMARY OF THE INVENTION

The present invention features compounds of formula (I)

or pharmaceutically acceptable salt forms, stereoisomers or tautomersthereof, wherein:

-   -   A is a monocyclic or bicyclic ring selected from the group        consisting of aryl, cycloalkyl, cycloalkenyl, heteroaryl and        heterocycle;    -   R¹ is cyclobutyl—N(R_(a))-, and is optionally substituted with        at least 1, 2 or 3 substituents each of which is independently        selected from the group consisting of alkyl, alkenyl, alkynyl,        oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl,        heteroaryl, heterocycle, arylalkyl, heteroarylalkyl,        alkoxyalkoxyalkyl, -(alkyl)(OR_(c)), -(alky)(NR_(c)R_(c)),        —SR_(c), —S(O)₂R_(c), —S(O)₂R_(c), —OR_(c)—N(R_(c))(R_(c)),        —C(O)R_(c), —C(O)OR_(c) and —C(O)NR_(c)R_(c);    -   R² and R³ are each independently selected from the group        consisting of hydrogen, alkenyl, alkynyl, alkoxyalkyl,        alkoxycarbonyl, alkyl, aryl, arylalkyl, heteroaryl, heterocycle,        heteroarylalkyl, cyano, halo, —N(R_(a))(R_(b)),        R_(a)R_(b)NC(O)—, —SR_(n), —S(O)R_(a), —S(O)₂R_(a) and        R_(a)C(O)—, wherein R² and R³ are each independently optionally        substituted with at least 1, 2 or 3 substituents each of which        is independently selected from the group consisting of R_(a),        alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl,        -(alkyl)(OR_(k)), -(alkyl)(NR_(a)R_(b)), —SR_(a), —S(O)R_(a),        —S(O)₂R_(a), —OR_(k), —N(R_(a))(R_(b)), —C(O)R_(a), —C(O)OR_(a)        and —C(O)NR_(a)R_(b);    -   alternatively, R² and R³, together with the carbon atoms to        which they are attached, form a five- or six-membered ring        selected from the group consisting of aryl, cycloalkyl,        heteroaryl and heterocycle, wherein each said aryl, cycloalkyl,        heteroaryl and heterocycle is optionally substituted with        (R⁶)_(m);    -   R⁴ is selected from the group consisting of alkoxy, aiylalkoxy,        aryloxy, halo, hydroxy, R_(a)R_(b)N—, N₃— and R_(c)S—, and is        optionally substituted with at least 1 or 2 substituents each of        which is independently selected from the group consisting of        halo, nitro, cyano, —OH, —NH₂, and —COOH;    -   R⁵ is independently selected at each occurrence from the group        consisting of alkenyl, alkoxy, alkyl, alkynyl, aryl, arylalkyl,        arylcarbonyl, aryloxy, azidoalkyl, formyl, halo, haloalkyl,        halocarbonyl, heteroaryl, heteroarylalkyl, heterocycle,        heterocyclealkyl, hydoxyalkyl, cycloalkyl, cyano, cyanoalkyl,        nitro, R_(a)R_(b)N—, R_(n)C(O)—, R_(a)S—, R_(a)(O)S—,        R_(n)(O)₂S—, R_(a)R_(b)Nalkyl-, R_(a)(O)SN(R_(f))-,        R_(a)SO₂N(R_(f))—, R_(a)(O)SN(R_(f))alkyl-,        R_(a)SO₂N(R_(f))alkyl-, R_(a)R_(b)NSO₂N(R_(f))—,        R_(a)R_(b)NSO₂N(R_(f))alkyl-, R_(a)R_(b)NC(O)—, R_(k)OC(O)—,        R_(k)OC(O)alkyl-, R_(k)Oalkyl-, R_(a)R_(b)NSO₂—,        R_(a)R_(b)NSO₂alkyl-, (R_(b)O)(R_(a))P(O)O— and —OR_(k), wherein        each R⁵ is independently optionally substituted at each        occurrence with at least 1, 2 or 3 substituents each of which is        independently selected from the group consisting of alkyl,        alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl,        haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl,        heteroarylalkyl, alkoxyalkoxyalkyl, -(alkyl)(OR_(e)),        -(alkyl)(NR_(c)R_(d)), —SR_(c), —S(O)R_(c), —S(O)₂R_(c),        —OR_(c), —N(R_(c))(R_(d)), —C(O)R_(c), —C(O)OR_(c) and        —C(O)NR_(c)R_(d);    -   R⁶ is independently selected at each occurrence from the group        consisting of alkyl, alkenyl, alkynyl, halo, cyano, nitro,        haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl,        heteroarylalkyl, heterocyclealkyl, -(alkyl)(OR_(k)),        -alkyl)(NR_(a)R_(b)), —SR_(a), —S(O)R_(a), —S(O)₂R_(n, —(OR)        _(k), —N(R_(a))(R_(b)), —C(O)R_(a), —C(O)OR_(a) and        —C(O)NR_(a)R_(b); wherein each R⁶ is independentiy optionally        substituted with at least 1, 2 or 3 substituents each of which        is independently selected from the group consisting of alkyl,        alkenyl, alkynyl, oxo, halo, haloalkyl, cyano, nitro, —OR_(a),        —NR_(a)R_(b), —SR_(a), —SOR_(a), —SO₂R_(a), —C(O)OR_(a),        —C(O)NR_(a)R_(b) and —NC(O)R_(a);    -   R_(a) and R_(b) are each independently selected at each        occurrence from the group consisting of hydrogen, alkenyl,        alkyl, alkylsulfanylalkyl, aryl, arylalkenyl, arylalkyl,        cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl,        cycloalkylalkyl, cycloalkylalkenyl, formylalkyl, haloalkyl,        heteroaryl, heteroarylalkenyl, heteroarylalkyl, heterocycle,        heterocyclealkenyl, heterocyclealkyl, hydroxyalkylcarbonyl,        nitroalkyl, R_(c)R_(d)N—, R_(p)O—. R_(p)Oalkyl-,        R_(c)R_(d)Nalkyl-, R_(c)R_(d)NC(O)alkyl-, R_(c)SO₂—,        R_(c)SO₂alkyl-, R_(c)C(O)—, R_(c)C(O)alkyl-, R_(c)OC(O)—,        R_(c)OC(O)alkyl-, R_(c)R_(d)NalkylC(O)—, R_(c)R_(d)NC(O)—,        R_(c)R_(d)NC(O)Oalkyl-, and R_(c)R_(d)NC(O)N(R_(c))alkyl-,        wherein R_(a) and R_(b) are each independently optionally        substituted at each occurrence with at least 1 or 2 substituents        each of which is independently selected from the group        consisting of alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro,        haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl,        heteroarylalkyl, alkoxyalkoxyalkyl, -(alkyl)(OR_(c)),        -(alkyl)(NR_(c)R_(d)), —SR_(c), —S(O)R_(c), —S(O)₂R_(c),        —OR_(c), —N(R_(c))(R_(d)), —C(O)R_(c), —C(O)OR_(c) and        —C(O)NR_(c)R_(d);    -   alternatively, R_(a) and R_(b)) together with the nitrogen atom        to which they are attached, form a three- to six-membered ring        selected from the group consisting of heteroaryl and        heterocycle, wherein the heteroaryl and heterocycle are each        independently optionally substituted at each occurrence with at        least 1, 2 or 3 substituents each of which is independently        selected from the group consisting of alkyl, alkenyl, alkynyl,        oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl,        heteroaryl, heterocycle, arylalkyl, heteroarylalkyl,        alkoxyalkoxyalkyl, -(alkyl)(OR_(c)), -(alkyl)(NR_(c)R_(d)),        -alkylSO₂NR_(c)R_(d), -alkyl C(O)NR_(c)R_(d), —SR_(c),        —S(O)R_(c), —S(O)₂R_(c), —OR_(c), N(R_(c))(R_(d)), —C(O)R_(c),        —C(O)OR_(c), and —C(O)NR_(c)R_(d);    -   R_(c) and R_(d) are each independently selected at each        occurrence from the group consisting of hydrogen, —NR_(f)R_(h),        —OR_(f), —CO(R_(f)), —SR_(f), —SOR_(f), —SO₂R_(f),        —C(O)NR_(f)R_(h), —C(O)OR_(f), alkenyl, alkyl, alkynyl,        cycloalkyl, cycloalkylalkyi, cycloalkenyl, cycloalkenylalkyl,        aryl, arylalkyl, haloalkyl, heteroaryl, heteroarylalkyl,        heterocycle and heterocyclealkyl; wherein each R_(c) and R_(d)        is independently optionally substituted at each occurrence with        at least 1, 2, or 3 substituents each of which is independently        selected from the group consisting of alkyl, alkenyl, alkynyl,        oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl,        heteroaryl, heterocycle, arylalkyl, heteroarylalkyl,        alkoxyalkoxyalkyl, -(alkyl)(OR_(f)), -(alkyl)(NR_(f)R_(h)),        —SR_(f), —S(O)R_(f), —S(O)₂R_(f), —OR_(f), —N(R_(f))(R_(h)),        —C(O)R_(f), —C(O)OR_(f), —C(O)NR_(f)R_(h), —C(O)N(H)NR_(f)R_(h),        —N(R_(c))C(O)OR_(f), —N(R_(c)) SO₂NR_(f)R_(h),        —N(R_(c))C(O)NR_(f)R_(h), -alkylN(R_(c))C(O)OR_(f),        -alkylN(R_(c))SO₂NR_(f)R_(h), and -alkylN(R_(c))C(O)NR_(f)R_(h);    -   alternatively, R_(c) and R_(d), together with the nitrogen atom        to which they are attached, form a three- to six-membered ring        selected from the group consisting of heteroaryl and        heterocycle, wherein the heteroaryl and heterocycle are each        independently optionally substituted at each occurrence with at        least 1, 2 or 3 substituents each of which is independently        selected from the group consisting of alkyl, alkenyl, alkynyl,        oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl,        heteroaryl, heterocycle, arylalkyl, heteroarylalkyl,        alkoxyalkoxyalkyl, -(alkyl)(OR_(f)), -(alkyl)(NR_(f)R_(h)),        —SR_(f), —S(O)R_(f), —SO₂R_(f), —OR_(f), —N(R_(f))(R_(h)),        —C(O)R_(f), —C(O)OR_(f) and —C(O)NR_(f)R_(h);    -   R_(c) is independently selected at each occurrence from the        group consisting of hydrogen, alkenyl, alkyl and cycloalkyl;    -   R_(f) and R_(h) are each independently selected at each        occurrence from the group consisting of hydrogen, alkyl,        alkenyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl,        cycloalkenyl, cycloalkenylalkyl, heterocycle, heterocyclealkyl,        heteroaryl and heteroarylalkyl; wherein each R_(f) and R_(h) is        independently optionally substituted at each occurrence with at        least 1, 2 or 3 substituents each of which is independently        selected from the group consisting of alkyl, alkenyl, alkynyl,        cyano, halo, oxo, nitro, aryl, arylalkyl, cycloalkyl,        cycloalkenyl, heterocycle, heteroaryl, heteroarylalkyl, —OH,        —O(alkyl), —NH₂, —N(H)(alkyl), —N(alkyl)₂, —S(alkyl),        —S(O)(alkyl), —SO₂alkyl, -alkyl—OH, -alkyl-O-alkyl, -alkylNH₂,        -alkylN(H)(alkyl), -alkylN(alkyl)₂, -alkylS(alkyl),        -alkylS(O)(alkyl), -alkylSO₂alkyl, —N(H)C(O)NH₂, —C(O)OH,        —C(O)O(alkyl), —C(O)alkyl, —C(O)NH₂, —C(O)NH₂, —C(O)N(H)(alkyl),        and —C(O)N(alkyl)₂;    -   alternatively, R_(f) and R_(h) together with the nitrogen atom        to which they are attached, form a three- to seven-membered ring        selected from the group consisting of heterocycle and        heteroaryl; wherein the heterocycle and heteroaryl are each        independently optionally substituted at each occurrence with at        least 1, 2 or 3 substituents each of which is independently        selected from the group consisting of alkyl, alkenyl, alkynyl,        cyano, halo, oxo, nitro, aryl, arylalkyl, cycloalkyl,        cycloalkenyl, heterocycle, heteroaryl, heteroaryialkyl, —OH,        —O(alkyl), —NH₂, —N(H)(alkyl), —N(alkyl)₂, —S(alkyl), —S(alkyl),        —S(O)(alkyl), -alkyl—OH, -alkyl-O-alkyl, -alkylNH₂,        -alkylN(H)(alkyl), -alkylS(alkyl), -alkylS(O)(alkyl),        -alkylSO₂alkyl, -alkylN(alkyl)₂, —N(H)C(O)NH₂, —C(O)OH,        —C(O)(alkyl), —C(O)alkyl, —C(O)NH₂, —C(O)NH₂, —C(O)N(H)(alkyl),        and —C(O)N(alkyl)₂;    -   R_(k) is independently selected at each occurrence from the        group consisting of hydrogen, alkenyl, alkyl, aryl, arylalkyl,        cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl,        cycloalkylalkyi, formylalkyl, haloalkyl, heteroaryl,        heteroarylalkyl, heterocycle, heterocyclealkyl, nitroalkyl,        R_(a)R_(b)Nalkyl-, R_(a)Oalkyl-, R_(a)R_(b)NC(O)—,        R_(a)R_(b)NC(O)alkyl, R_(a)S-, R_(a)S(O)—, R_(a)SO₂- ,        R_(a)Salkyl-, R_(a)(O)Salkyl-, R_(a)SO₂alkyl-, R_(a)OC(O)—,        R_(a)OC(O)alkyl-, R_(a)C(O)—, and R_(a)C(O)alkyl-, wherein each        R_(k) is independently optionally substituted at each occurrence        with at least 1, 2, or 3 substituents each of which is        independently selected from the group consisting of alkyl,        alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl,        haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl,        heteroarylalkyl, alkoxyalkoxyalkyl, -(alkyl)(OR_(c)),        -(alkyl)(NR_(c)R_(d)), —SR_(c), —S(O)R_(c), —SO₂R_(c), —OR_(c),        —N(R_(c))(R_(d)), —C(O)Rc, —C(O)OR_(c) and —C(O)NR_(c)R_(d);    -   R_(p) is independently selected at each occurrence from the        group consisting of hydrogen, alkenyl, aikyl, aryl, arylalkyl,        cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl,        cycloalkylalkyl, formylalkyl, haloalkyl, heteroaryl,        heteroarylalkyl, heterocycle, heterocyclealkyi, and nitroalkyl,        wherein each R_(p) is independently optionally substituted at        each occurrence with at least 1, 2, or 3 substituents each of        which is independently selected from the group consisting of        alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl,        haloaikoxy, aryl, heteroaryl, heterocycle, arylalkyl,        heteroarylalkyl, alkoxyalkoxyalkyl, -(alkyl)(OR_(c)),        -(alkyl)(NR_(c)R_(d)), —SR_(c), —S(O)R₂, —SO₂R_(c), —OR_(c),        —N(R_(c))(R_(d)), —C(O)R_(c), —C(O)OR_(c) and —C(O)NR_(c)R_(d);    -   m is 1, 2, 3, or 4;    -   n is 1, 2, 3, or 4; and    -   wherein at least one R⁵ is R_(a)SO₂N(R_(f))alkyl-.

In one embodiment, A is a monocyclic ring selected from the groupconsisting of aryl and heteroaryl.

In another embodiment, A is heteroaryl, and R² and R³ together with thecarbon atoms to which they are attached form a five- or six-memberedring selected from the group consisting of phenyl, pyridyl, pyrimidinyl,pyridazinyl, thienyl, furanyl, pyrrolyi, pyrazolyl, oxazolyl, thiazolyl,imidazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl,tetrazolyl, cyclopentyl and cyclohexyl.

In yet another embodiment, A is thienyl, and R² and R³ together with thecarbon atoms to which they are attached form a five- or six-memberedring selected from the group consisting of phenyl, pyridyl, pyrimidinyl,pyridazinyl, thienyl, furanyl, pyrrolyi, pyrazolyl, oxazolyl, thiazolyl,imidazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl,tetrazolyl, cyclopentyl and cyclohexyl. For example, A can be thienyl,and R² and R³, together with the carbon atoms to which they areattached, form a phenyl ring.

In still another embodiment, A is pyridyl, phenyl, thienyl, imidazolyl,benzimidazolyl, benzoxazolyl or benzoxazinyl, R² and R³ together withthe carbon atoms to which they are attached form a five- or six-memberedring selected from the group consisting of phenyl, pyridyl, thienyl,pyrimidinyl, pyrazolyl, pyridazinyl, cyclohexyl and cyclopentyl, and R⁴is hydroxy.

In a further embodiment, A is pyridyl, phenyl, thienyl, imidazolyl,benzimidazolyl, benzoxazolyl or benzoxazinyl, R² and R³ together withthe carbon atoms to which they are attached form a five- or six-memberedring (hereinafter the “B” ring) selected from the group consisting ofphenyl, pyridyl, thienyl, pyrimidinyl, pyrazolyl, pyridazinyl,cyclohexyl and cyclopentyl, R⁴ is hydroxy, R¹ is cyclobutyl—N(H)-, n is1, and R⁵ is R_(a)SO₂N(H)-R_(j)-, wherein R_(a) is defined above or,preferably, CH₃- or C₂-C₄alkyl, and R_(j) is —CH₂- or C₂-C₄alkylene. Inone example, A is phenyl, and the B ring is pyridyl. In another example,A is phenyl, and the B ring is thienyl. In yet another example, A isphenyl, and the B ring is phenyl. In a further example, A is thienyl(e.g.,

and the B ring is phenyl. In still another example, A is thienyl (e.g.,

and the B ring is pyridyl. In still yet another example, A is pyridyl,and the B ring is phenyl. The B ring can be optionally substituted withat least one R⁶ which is independently selected at each occurrence fromthe group consisting of alkyl, alkenyl, alkynyl, halo, cyano, nitro,haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl,heteroarylalkyl, heterocyclealkyl, -(alkyl)(OR_(k)),-(alkyl)(NR_(a)R_(b)), —SR_(a), —S(O)R_(a), —SO₂R_(a), —OR_(k),—N(R_(a))(R_(b)), —C(O)R_(a), —C(O)OR_(a) and —C(O)NR_(a)R_(b). Each R⁶can also be independentiy optionally substituted with at least 1, 2 or 3substituents each of which is independently selected from the groupconsisting of alkyl, alkenyl, alkynyl, oxo, halo, haloalkyl, cyano,nitro, —OR_(a), —NR_(a)R_(b), —SR_(a), —SOR_(a), —SO₂R_(a), —C(O)OR_(a),—C(O)NR_(a)R_(b) and —NC(O)R_(a).

In yet another embodiment, a compound of the present invention isN-[(3-{1-[(cyclobutyl)amino]-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-yl}-1,1-dioxo-1,4-dihydro-1λ⁶-thieno[2,3-e][1,2,4]thiadiazin-7-yl)methyl]methanesulfonamide (hereinafter “compound I”). The presentinvention has discovered that compound I has unexpectedly improvedpharmacokinetic profiles, including increased concentrations of thecompounds in liver after oral administration, as compared to othercompounds.

In another embodiment, the present invention provides pure orsubstantially pure compound I, or a pure or substantially purepharmaceutically acceptable salt, stereoisomer or tautomer thereof.

The present invention also features pharmaceutical compositionscomprising the compounds of the present invention or pharmaceuticallyacceptable salt forms thereof, and a pharmaceutically acceptablecarrier. A pharmaceutical composition of the present invention caninclude at least 1,2, 3 or more compounds of the present invention and,optionally, at least 1, 2, 3 or more other therapeutic agents, such asimmune modulators or other anti-viral agents (e.g., anti-HCV, anti-HBVor anti-HIV agents) or a combination thereof.

The present invention further features methods of using the compounds ofthe present invention to inhibit HCV RNA-dependent RNA polymerase. Themethods comprise contacting a compound of the present invention (e.g.,compound I), or a pharmaceutically acceptable salt, stereoisomer ortautomer thereof, with an HCV RNA-dependent RNA polymerase, therebyinhibiting the activity of the RNA polymerase.

In addition, the present invention features methods of using thecompounds of the present invention to inhibit HCV replication. Themethods comprise contacting HCV virus, or cells infected with HCV virus,with an effective amount of a compound of the present invention (e.g.,compound I) or a pharmaceutically acceptable salt, stereoisomer ortautomer thereof, thereby inhibiting HCV virus replication.

The present invention also features methods of using the compounds ofthe present invention to treat or prevent HCV infection. The methodscomprise administering to a patient in need of such treatment aneffective amount of a compound of the present invention (e.g., compoundI) or a pharmaceutically acceptable salt, stereoisomer or tautomerthereof, thereby treating or preventing HCV infection in the patient.

The present invention further provides processes of making the compoundsof the present invention, and intermediates employed in the processes.

Other features, objects, and advantages of the present invention areapparent in the detailed description that follows. It should beunderstood, however, that the detailed description, while indicatingpreferred embodiments of the invention, are given by way of illustrationonly, not limitation. Various changes and modifications within the scopeof the invention will become apparent to those skilled in the art fromthe detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

The drawing is provided for illustration, not limitation.

FIG. 1 shows liver concentrations of compounds I, II and III atdifferent time points after oral dosing in rats.

DETAILED DESCRIPTION OF THE INVENTION

As used in the present specification the following terms have themeanings indicated below,

As used herein, the singular forms “a” and “an” may include pluralreference unless the context clearly dictates otherwise.

The term “alkyl,” as used herein, refers to a saturated straight orbranched hydrocarbon chain group containing 1, 2, 3, 4, 5, 6, 7, 8, 9 or10 carbon atoms. Examples of alkyl groups include butyl, methyl,2-methylbutyl, and the like.

The terms “alkylene” or “alkylenyl,” as used herein, refer to a divalentgroup derived from a straight or branched saturated hydrocarbon chainhaving 1, 2, 3,4, 5, 6, 7, 8, 9 or 10 carbon atoms. Representativeexamples of aikylene include, but are not limited to, —CH₂—, —CH₂CH₂—,—CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and —CH₂CH(CH₃)CH₂—.

The term “alkenyl,” as used herein, refers to a straight or branchedhydrocarbon chain group of 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atomscontaining at least one carbon-carbon double bond. Examples of alkenylgroups include allyl, propenyl, 3-methyl-2-butenyl, and the like.

The term “alkynyl,” as used herein, refers to a straight or branchedchain hydrocarbon of 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atomscontaining at least one carbon-carbon triple bond. Examples of alkynylgroups include ethynyl, 2-methyl-3-butynyi, 3-pentynyl, and the like.

The term “alkoxy,” as used herein, refers to an alkyl group attached tothe parent molecular moiety through an oxygen atom. Examples of alkoxygroups include tert-butoxy, methoxy, isopropoxy, and the like.

The term “alkoxyalkoxy” as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through anotheralkoxy group, as defined herein. Representative examples of alkoxyalkoxyinclude, but are not limited to, tert-butoxy methoxy, 2-ethoxyethoxy,2-methoxyethoxy, and methoxymethoxy.

The term “alkoxyalkoxyalkyl” as used herein, means an alkoxyalkoxygroup, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofalkoxyalkoxyalkyl include, but are not limited to, tert-butoxymethoxymethyl, ethoxymethoxymethyl, (2-methoxyethoxy)methyl, and2-(2-methoxyethoxy)ethyl.

The term “alkoxyalkyl,” as used herein, refers to an alkyl groupsubstituted by at least one alkoxy group.

The term “alkoxycarbonyl,” as used herein, refers to an alkoxy groupattached to the parent molecular moiety through a carbonyl group.Examples of alkoxycarbonyl groups include tert-butoxycarbonyl,ethoxycarbonyl, methoxycarbonyl, and the like.

The term “alkoxycarbonylalkyl,” as used herein, refers to analkoxycarbonyl group attached to the parent molecular moiety through analkyl group.

The term “alkylcarbonyl,” as used herein, refers to an alkyl groupattached to the parent molecular moiety through a carbonyl group.Examples of alkylcarbonyl groups include acyl, butanoyl,2,2-dimethylpropanoyl, and the like.

The term “alkylcarbonylaikyi” as used herein, means an alkylcarbonylgroup, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofalkylcarbonylaikyi include, but are not limited to, 2-oxopropyl,3,3-dimethyl-2-oxopropyl, 3-oxobutyl, and 3-oxopentyl,

The term “alkylsulfanyl,” as used herein, refers to an alkyl groupattached to the parent molecular moiety through a sulfur atom. Examplesof alkylsulfanyl groups include methylsulfanyl, (1-methylethyl)sulfanyl,(2-methylpropyl)sulfanyl, and the like.

The term “alkylsulfanylalkyl,” as used herein, refers to analkylsulfanyl group attached to the parent molecular moiety through analkyl group.

The term “alkylsulfinyl,” as used herein, refers to an alkyl groupattached to the parent molecular moiety through a —S(O)— group,

The term “alkylsulfinylalkyl,” as used herein, refers to analkylsulfinyl group attached to the parent molecular moiety through analkyl group.

The term “alkylsulfonyl,” as used herein, refers to an alkyl groupattached to the parent molecular moiety through a —SO₂— group.

The term “alkylsulfonylalkyl,” as used herein, refers to analkylsulfonyl group attached to the parent molecular moiety through analkyl group.

The term “aryl” as used herein, refers to a phenyl group, or a bicyclicor tricyclic hydrocarbon fused ring systems wherein one or more of therings is a phenyl group. Bicyclic fused ring systems have a phenyl groupfused to a monocyclic cycloalkenyl group, as defined herein, amonocyclic cycloalkyl group, as defined herein, or another phenyl group.Tricyclic fused ring systems are exemplified by a bicyclic fused ringsystem fused to a monocyclic cycloalkenyl group, as defined herein, amonocyclic cycloalkyl group, as defined herein, or another phenyl group.Examples of aryl groups include anthracenyl, azulenyl, fluorenyl,indanyl, indenyl, naphthyl, phenyl, tetrahydronaphthyl, and the like.The aryl groups of the present invention can be connected to the parentmolecular moiety through any substitutable carbon atom of the group. Thearyl groups of the present invention can be substituted with 0, 1, 2, 3,4 or 5 substituents independently selected from the group consisting ofalkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro, oxo, —OR_(a),—OC(O)R₁, —OC(O)OR_(a), —OC(O)NR_(a)R_(b), —OSO₂R_(a), —OSO₂NR_(a)R_(b),—SR_(a), —SOR_(a), —SO₂R_(a), —SO₂OR_(a), —SO₂NR_(a)R_(b), —NR_(a)R_(b),—N(R_(c))C(O)R_(a), —N(R_(c))C(O)OR_(a), —N(R_(c))C(O)NR_(a)R_(b),—N(R_(c))SO₂R_(a)—N(R_(c))SO₂NR_(a)R_(b),—N(R_(c))SO₂N(R_(c))C(O)OR_(a), —C(O)R_(a), —C(O)OR_(a),—C(O)NR_(a)R_(b), cycloalkyl, cycloalkenyl, heterocycle, a second arylgroup and heteroaryl; wherein each of the alkyl, alkenyl and alkynyl isindependently substituted with 0, 1, 2 or 3 substituents independentlyselected from the group consisting of cyano, formyl, halo, nitro, oxo,-OR_(a), —OC(O)R_(a), —OC(O)OR_(a), —OC(O)NR_(a)R_(b), —OSO₂R_(a),—OSO₂NR_(a)R_(b), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂OR_(a),—SO₂NR_(a)R_(b), —NR_(a)R_(b), —N(R_(c)) C(O)R_(a), —N(R0)C(O)OR_(a),—N(R_(c))C(O)NR_(a)R_(b), —N(R_(c))SO₂R_(a), —N(R_(c))SO₂NR_(a)R_(b),—N(R_(c))SO₂N(R_(c))C(O)OR_(a), —C(O)R_(a), —C(O)OR_(a),—C(O)NR_(a)R_(b), cycloalkyl, cycloalkenyl, heterocycle, a second arylgroup and heteroaryl; wherein R_(a), R_(b) and R_(c) are definedhereinabove, and wherein the second aryl group, the heteroaryl, thecycloalkyl, the cycloalkenyl and the heterocycle can be substituted with0, 1, 2 or 3 substituents independently selected from the groupconsisting of —OH, —O(alkyl), alkyl, alkenyl, alkynyl, cyano, formyl,halo, haloalkoxy, haloalkyl, nitro, —NH₂, —N(H)(alkyl), —N(alkyl)₂,—C(O)OH, —C(O)O(alkyl), —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂ andoxo,

The term “arylalkenyl,” as used herein, refers to an aryl group attachedto the parent molecular moiety through an alkenyl group.

The term “arylalkoxy,” as used herein, refers to an arylalkyl groupattached to the parent molecular moiety through an oxygen atom.

The term “arylalkyl,” as used herein, refers to an aryl group attachedto the parent molecular moiety through an alkyl group,

The term “arylcarbonyl,” as used herein, refers to an aryl groupattached to the parent molecular moiety through a carbonyl group.

The term “aryicarbonylaikyl” as used herein, means an arylcarbonylgroup, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein.

The term “aryloxy,” as used herein, refers to an aryl group attached tothe parent molecular moiety through an oxygen atom.

The term “aiyloxyaikyl,” as used herein, refers to an aryloxy groupattached to the parent molecular moiety through an alkyl atom.

The term “aryisulfanyl,” as used herein, refers to an aryl groupattached to the parent molecular moiety through a sulfur atom.

The term “arylsulfanylalkyl,” as used herein, refers to an aryisulfanylgroup attached to the parent molecular moiety through an alkyl group.

The term “arylsulfonyl,” as used herein, refers to an aryl groupattached to the parent molecular moiety through a suifonyl group.

The term “arylsulfonylalkyl,” as used herein, refers to an arylsulfonylgroup attached to the parent molecular moiety through an alkyl group.

The term “carboxy,” as used herein, refers to —CO₂H.

The term “carboxyalkyl,” as used herein, refers to a carboxy groupattached to the parent molecular moiety through an alkyl group.

The term “cyano,” as used herein, refers to —CN.

The term “cyanoalkyl,” as used herein, refers to a cyano group attachedto the parent molecular moiety through an alkyl group.

The term “cycloalkenyl,” as used herein, refers to a non-aromatic,partially unsaturated, monocyclic, bicyclic or tricyclic ring system,having three to fourteen carbon atoms and zero heteroatom, Examples ofcycloalkenyl groups include cyclohexenyl, octahydronaphthalenyl,norbornylenyl, and the like. The cycloalkenyl groups of the presentinvention can be substituted with 0, 1,2, 3, 4 or 5 substituentsindependently selected from the group consisting of alkyl, alkenyl,alkynyl, cyano, formyl, halo, nitro, oxo, —OR_(a), —OC(O)R_(a),—OC(O)OR_(a), —OC(O)NR_(a)R_(b), —OSO₂R_(a), —OSO₂NR_(a)R_(b), —SR_(a),—SOR_(a), —SO₂R_(a), —SO₂OR_(a), —SO₂NR_(a)R_(b), —NR_(a)R_(b),—N(R_(c))C(O)R_(a), —N(R_(c))C(O)OR_(a), —N(R_(c))C(O)NR_(a)R_(b),—N(R_(a))SO₂R_(a), —N(R_(c))SO₂NR_(a)R_(b),—N(R_(c))SO₂N(R_(c))C(O)OR_(a), —C(O)R_(a), —C(O)OR_(a),—C(O)NR_(a)R_(b) cycloalkyl, a second cycloalkenyl, heterocycle, aryl,heteroaryl and ethylenedioxy; wherein each of the alkyl, alkenyl andalkynyl is independently substituted with 0, 1, 2 or 3 substituentsindependently selected from the group consisting of cyano, formyl, halo,nitro, oxo, —OR_(a), —OC(O)R_(a), —OC(O)OR_(a), —OC(O)NR_(a)R_(b),—OSO₂R_(a), —OSO₂NR_(a)R_(b), —SR_(a), —SOR_(a), —SO₁R_(a), —SO₂OR_(a),—SO₂NR_(a)R_(b), —NR_(a)R_(b), —N(R_(c))C(O)R_(a), —N(R_(c))C(O)OR_(a),—N(R_(c))C(O)NR_(a)R_(b), —N(R_(c))SO₂R_(a), —N(R_(c))SO₂NR_(a)R_(b),—N(R_(c))SO₂N(R_(c))C(O)OR_(a), —C(O)R_(a), —C(O)OR_(a),—C(O)NR_(a)R_(b), cycloalkyl, a second cycloalkenyl, heterocycle, aryland heteroaryl; wherein R_(a), R_(b) and R_(c) are defined hereinabove,and wherein the cycloalkyl, the second cycloalkenyl, the heterocycle,the aryl and the heteroaryl can be substituted with 0, 1, 2 or 3substituents independently selected from the group consisting of —OH,—O(alkyl), alkyl, alkenyl, alkynyl, cyano, formyl, halo, oxo,haloalkoxy, haloalkyl, nitro, oxo, —NH₂, —N(H)(alkyl), —N(alkyl)₂,—C(O)OH, —C(O)O(alkyl), —C(O)NH₂, —C(O)N(H)(alkyl), and —C(O)N(alkyl)₂.

The term “cycloalkenylalkyl,” as used herein, refers to a cycloalkenylgroup attached to the parent molecular moiety through an alkyl group

The term “cycloalkyl,” as used herein, refers to a saturated monocyclic,bicyclic, or tricyclic hydrocarbon ring system having three to fourteencarbon atoms and zero heteroatom. Examples of cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,bicyclo[3.1.1]heptyl, 6,6-diinethylbcyclo[3.1.1]heptyl, adamantyi, andthe like. The cycloalkyl groups of the present invention can besubstituted with 0, 1, 2, 3, 4 or 5 substituents independently selectedfrom the group consisting of alkyl, alkenyl, alkynyi, cyano, formyl,halo, nitro, oxo, —OR_(a), —OC(O)R_(a), —OC(O)OR_(a), —OC(O)NR_(a)R_(b),—OSO₂R_(a), —OSO₂NR_(a)R_(b), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂OR_(a),—SO₂NR_(a)R_(b), —NR_(a)R_(b), —N(R_(a))C(O)R_(a), —N(R_(c))C(O)OR_(a),—N(R_(c))C(O)NR_(a)R_(b), —N(R_(c))SO₂R_(a), —N(R_(c))SO₂NR_(a)R_(b),—N(R_(c))SO₂N(R_(c))C(O)OR_(a), —C(O)R_(a), —C(O)OR_(a),—C(O)NR_(a)R_(b), a second cycloalkyl, cycloalkenyl, heterocycle, aryl,heteroaryl and ethylenedioxy; wherein each of the alkyl, alkenyl andalkynyi is independently substituted with 0, 1, 2 or 3 substituentsindependently selected from the group consisting of cyano, formyl, halo,nitro, oxo, —OR_(a), —OC(O)R_(a), —OC(O)OR_(a), —OC(O)NR_(a)R_(b),—OSO₂R_(a), —OSO₂NR_(a)R_(b), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂OR_(a),—SO₂NR_(a)R_(b) , —NR_(a)R_(b), —N(R_(c))C(O)R_(a), —N(R_(c))C(O)OR_(a),—N(R_(c))C(O)NR_(a)R_(b), —N(R_(a))SO₂R_(a), —N(R_(c))SO₂NR_(a)R_(b),—N(R_(c))SO₂(R_(a))C(O)OR_(a), —C(O)R_(a), —C(O)OR_(a),—C(O)NR_(a)R_(b), a second cycloalkyl, cycloalkenyl, heterocycle, aryland heteroaryl; wherein R_(a), R_(b) and R_(c) are defined hereinabove,and wherein the second cycloalkyl, the cycloalkenyl, the heterocycle,the aryl and the heteroaryl can be substituted with 0, 1,2 or 3substituents independently selected from the group consisting of —OH,—O(alkyl), alkyl, alkenyl, alkynyl, cyano, formyl, halo, haloalkoxy,haloalkyl, nitro, oxo, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —C(O)OH,—C(O)(alkyl), —C(O)NH₂, —C(O)N(H)(alkyl), and —C(O)N(alkyl)₂,

The term “cycloalkylalkenyl,” as used herein, refers to a cycloalkylgroup attached to the parent molecular moiety through an alkenyl group.

The term “cycloalkylalkyi,” as used herein, refers to a cycloalkyl groupattached to the parent molecular moiety through an alkyl group

The term “formyl,” as used herein, refers to —CHO.

The term “formylalkyl,” as used herein, refers to a formyl groupattached to the parent molecular moiety through an alkyl group.

The terms “halo,” and “halogen,” as used herein, refer to F, CI, Br, andI.

The term “haloalkoxy,” as used herein, refers to a haloalkyl groupattached to the parent molecular moiety through an oxygen atom.

The term “haloalkoxyalkyl,” as used herein, refers to a haloalkoxy groupattached to the parent molecular moiety through an alkyl group.

The term “haloalkyl,” as used herein, refers to an alkyl groupsubstituted by one, two, three, or four halogen atoms.

The term “heteroaryl,” as used herein, refers to an aromatic five- orsix-membered ring where at least one atom is selected from the groupconsisting of N, O, and S, and the remaining atoms are carbon. The term“heteroaryl” also includes bicyclic systems where a heteroaryl ring isfused to a phenyl group, a monocyclic cycloalkyl group, as definedherein, a heterocycle group, as defined herein, or an additionalheteroaryl group. The term “heteroaryl” also includes tricyclic systemswhere a bicyclic system is fused to a phenyl group, a monocycliccycloalkyl group, as defined herein, a heterocycle group, as definedherein, or an additional heteroaryl group. The heteroaryl groups areconnected to the parent molecular moiety through any substitutabiecarbon or nitrogen atom in the groups. Examples of heteroaryl groupsinclude benzothienyl, benzoxazolyl, benzimidazolyl, benzoxadiazolyl,dibenzofuranyl, dihydrobenzothiazolyl, furanyl, imidazolyl, indazolyl,indolyl, isoindolyl, isoxazolyl, isoquinolinyl, isothiazolyl,oxadiazolyl, oxazolyl, thiazolyl, thienopyridinyi, thienyl, triazolyl,thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidtnyl, pyrazinyl,pyrazolyl, pyrrolyi, quinolinyl, tetrahydroquinolinyl,tetrahydropyranyl, triazinyl, and the like. The heteroaryl groups of thepresent invention can be substituted with 0, 1, 2, 3, 4 or 5substituents independently selected from the group consisting of alkyl,alkenyl, alkynyl, cyano, formyl, halo, nitro, oxo, —OR_(a), —OC(O)R_(a),—OC(O)OR_(a), —OC(O)NR_(a)R_(b), —OSO₂R_(a), —OSO₂NR_(a)R_(b), —SR_(a),—SOR_(a), —SO₂R_(a), —SO₂OR_(a), —SO₂NR_(a)R_(b), —NR_(a)R_(b),—N(R_(c))C(O)R_(a), —N(R_(c))C(O)OR_(a), —N(R_(c))C(O)NR_(a)R_(b),—N(R_(c))SO₂R_(a), —N(R_(c))SO₂NR_(a)R_(b),—N(R_(c))SO₂N(R_(c))C(O)OR_(a), —C(O)R_(a), —C(O)OR_(a),—C(O)NR_(a)R_(b), cycloalkyl, cycloalkenyl, heterocycle, aryl and asecond heteroaryl group; wherein each of the alkyl, alkenyl and alkynylis independently substituted with 0, 1, 2 or 3 substituentsindependently selected from the group consisting of cyano, formyl, halo,nitro, oxo, —OR_(a), —OC(O)R_(a), —OC(O)OR_(a), —OC(O)NR_(a)R_(b),—OSO₂R_(a), —OSO₂NR_(a)R_(b), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂OR_(a),—SO₂NR_(a)R_(b), —NR_(a)R_(b), —N(R_(c))C(O)R_(a), —N(R_(c))C(O)OR_(a),—N(R_(c))C(O)NR_(a)R_(b), —N(R_(c))SO₂R_(a), —N(R_(c))SO₂NR_(a)R_(b),—N(R_(c))SO₂N(R_(c))C(O)OR_(a), —C(O)R_(a), —C(O)OR_(a),—C(O)NR_(a)R_(b), cycloalkyl, cycloalkenyl, heterocycle, aryl and asecond heteroaryl group; wherein R_(a), R_(b) and R_(c) are definedhereinabove, and wherein the second heteroaryl group, the aryl, thecycloalkyl, the cycloalkenyl and the heterocycle can be independentlysubstituted with 0, 1,2 01 3 substituents independently selected fromthe group consisting of —OH, —O(alkyl), alkyl, alkenyl, alkynyl, cyano,formyl, halo, haloalkoxy, haloalkyl, nitro, —NH₂, —N(H)(alkyl),—N(alkyl)₂, —C(O)OH, —C(O)(O)(alkyl), —C(O)NH₂, —C(O)N(H)(alkyl),—C(O)N(alkyl)₂ and oxo. In addition, the nitrogen heteroatoms can beoptionally quaternized or oxidized to the N-oxide,. Also, the nitrogencontaining rings can be optionally N-protected,

The term “heteroarylalkenyl,” as used herein, refers to a heteroarylgroup attached to the parent molecular moiety through an alkenyl group,

The term “heteroarylalkyl,” as used herein, refers to a heteroaryl groupattached to the parent molecular moiety through an alkyl group.

The term “heteroarylsulfonyl,” as used herein, refers to a heteroarylgroup attached to the parent molecular moiety through a sulfonyl group.

The term “heteroarylsulfonylalkyl,” as used herein, refers to aheteroarylsulfonyl group attached to the parent molecular moiety throughan alkyl group.

The term “heterocycle,” as used herein, refers to cyclic, non-aromatic,saturated or partially unsaturated, three, four, five-, six-, orseven-membered rings containing at least one atom selected from thegroup consisting of oxygen, nitrogen, and sulfur. The term “heterocycle”also includes bicyclic systems where a heterocycle ring is fused to aphenyl group, a monocyclic cycloalkenyl group, as defined herein, amonocyclic cycloalkyl group, as defined herein, or an additionalmonocyclic heterocycle group The term “heterocycle” also includestricyclic systems where a bicyclic system is fused to a phenyl group, amonocyclic cycloalkenyl group, as defined herein, a monocycliccycloalkyl group, as defined herein, or an additional monocyclicheterocycle group. The heterocycle groups of the invention are connectedto the parent molecular moiety through any substitutable carbon ornitrogen atom in the group. Examples of heterocycle groups includebenzoxazinyl, dihydroindolyl, dihydropyridinyl, 1,3-dioxanyl,1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyi, morpholinyl, piperazinyl,pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl,tetrahydropyranyl, and the like. The heterocycle groups of the presentinvention can be substituted with 0, 1,2, 3, 4 or 5 substituentsindependently selected from the group consisting of alkyl, alkenyl,alkynyl, cyano, formyl, halo, nitro, oxo, -OR_(a), —OC(O)R_(a),—OC(O)OR_(a), —OC(O)NR_(a)R_(b), —OSO₂R_(a), —OSO₂NR_(a)R_(b), —SR_(a),—SOR_(a), —SO₂R_(a), —SO₂OR_(a), —SO₂NR_(a)R_(b), —NR_(a)R_(b),—N(R_(c))C(O)R_(a), —N(R_(c))C(O)OR_(a), —N(R_(c))C(O)NR_(a)R_(b),—N(R_(c))SO₂R_(a), —N(R_(c))SO₂NR_(a)R_(b),—N(R_(c))SO₂N(R_(c))C(O)OR_(a), —C(O)R_(a), —C(O)OR_(a),—C(O)NR_(a)R_(b), cycloalkyl, cycloalkenyl, a second heterocycle, aryl,heteroaryl and ethylenedioxy; wherein each of the alkyl, alkenyl andalkynyl is independently substituted with 0, 1, 2 or 3 substituentsindependently selected from the group consisting of cyano, formyl, halo,nitro, oxo, —OR_(a), —OC(O)R_(a), —OC(O)OR_(a), —OC(O)NR_(a)R_(b),—OSO₂R_(a), —OSO₂NR_(a)R_(b), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂OR_(a),—SO₂NR_(a)R_(b), —NR_(a)R_(b), —N(R_(c))C(O)R_(a), —N(R_(c))C(O)OR_(a),—N(R_(c))C(O)NR_(a)R_(b), —N(R_(c))SO₂R_(a), —N(R_(c))SO₂NR_(a)R_(b),—N(R_(c))SO₂N(R_(c))C(O)OR_(a), —C(O)R_(a), —C(O)OR_(a),—C(O)NR_(a)R_(b), cycloalkyl, cycloalkenyl, a second heterocycle, aryland heteroaryl; wherein R_(a), R_(b) and R_(c) are defined hereinabove,and wherein the cycloalkyl, cycloalkenyl, the second heterocycle, thearyl and the heteroaryl can be independently substituted with 0, 1, 2 or3 substituents independently selected from the group consisting of —OH,—O(alkyl), alkyl, alkenyl, alkynyl, cyano, formyl, halo, haloaikoxy,haloalkyl, nitro, oxo, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —C(O)OH,—C(O)(alkyl), —C(O)NH₂, —C(O)N(H)(alkyl), and —C(O)N(alkyl)₂. Inaddition, the nitrogen heteroatoms can be optionally quatemized oroxidized to the N-oxide, Also, the nitrogen containing heterocyclicrings can be optionally N-protected.

The term “hetetocyclealkenyl,” as used herein, refers to a heterocyclegroup attached to the parent molecular moiety through an alkenyl group,

The term “heterocyclealkyi,” as used herein, refers to a heterocyclegroup attached to the parent molecular moiety through an alkyl group,

The term “heterocyclecarbonyl” as used herein, means a heterocycle, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofheterocyclecarbonyl include, but are not limited to,pyrrolidinylcarbonyl and piperazin-1-ylcarbonyl

The term “hydroxy,” as used herein, refers to —OH.

The term “hydroxyalkyl,” as used herein, refers to an alkyl groupsubstituted by at least one hydroxy group.

The term “nitro,” as used herein, refers to —NO₂.

The term “nitroalkyl,” as used herein, refers to an alkyl groupsubstituted by at least one nitro group

The term “oxo,” as used herein, refers to —O.

The term “sulfanyl,” as used herein, refers to —S—,

The term “sulfinyl,” as used herein, refers to —SO—.

The term “sulfonyl,” as used herein, refers to —SO₂.

It is understood that alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkyl,alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl,alkylcarbonyalkyl, alkynyl, alkylsulfanyl, alkylsulfanylalkyl,alkylsulfinyl, alkylsulfinylalkyl, alkylsulfonyl, alkylsulfonylalkyl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, arylsulfanylalkyl,arylsulfonylalkyl, carboxyalkyl, cyanoalkyl, cycloalkenylalkyl,cycloalkenylaikenyl, cycloalkylalkyl, formylalkyl, haloaikoxy,haloalkoxyalkyl, haloalkyl, heteroarylalkenyl, heteroarylalkyl,heterosulfonylalkyl, heterocyclealkenyl, heterocyclealkyl, hydroxyalkyland nitroalkyl may optionally be substituted.

The number of carbon atoms in a hydrocarbyl substituent can be indicatedby the prefix “C_(x)-C_(y),” where x is the minimum and y is the maximumnumber of carbon atoms in the substituent. A prefix attached to amultiple-component substituent only applies to the first component thatimmediately follows the prefix. To illustrate, the term “alkylaryl”contains two components: alkyl and aryl. Thus, C₁-C₆alkylaryl refers toa C₁-C₆alkyl appended to the parent molecular moiety through an arylgroup

The present invention features compounds of formula (I) as describedabove, and pharmaceutically acceptable salts, stereoisomers or tautomersthereof.

In one embodiment, the present invention provides a compound of formula(II)

or a pharmaceutically acceptable salt form, stereoisomer or tautomerthereof wherein:

-   -   R¹ is cyclobutyl-N(H)—;    -   R⁴ is hydroxy;    -   R⁵ is R_(a)SO₂NH—R_(j)—, wherein R_(a) is as defined immediately        below or, preferably, CH₃- or C₂-C₄(alkyl, and R_(j) is —CH₂—or        C₂-C₄alkylene;    -   R⁶ is independently selected at each occurrence from the group        consisting of alkyl, alkenyl, alkynyl, halo, cyano, nitro,        haloalkyl, haloaikoxy, aryl, heteroaryl, heterocycle, arylalkyl,        heteroarylalkyl, heterocyclealkyi, -(alkyl)(OR_(k)),        -(alkyl)(NR_(a)R_(b)), —SR_(a), —S(O)R_(a), —S(O)₂R_(a),        —OR_(k), —N(R_(a))(R_(b)), —C(O)R_(a), —C(O)OR_(a) and        —C(O)NR_(a)R_(b); wherein each R⁶ is independently optionally        substituted at each occurrence with at least 1, 2 or 3        substituents each of which is independently selected from the        group consisting of alkyl, alkenyl, alkynyl, oxo, halo,        haloalkyl, cyano, nitro, —OR_(a), —NR_(a)R_(b), —SR_(a),        —SOR_(a), —SO₂R_(a), —C(O)OR_(a), —C(O)NR_(a)R_(b) and        —NC(O)R_(a);    -   R_(a) and R_(b) are each independently selected at each        occurrence from the group consisting of hydrogen, alkenyl,        alkyl, alkylsulfanylalkyl, aryl, arylalkenyl, arylalkyl,        cyanoalkyl, cycloalkenyl, cycloaikenyialkyl, cycloalkyl,        cycloalkylalkyl, cycloalkylalkenyl, formylalkyl, haloalkyl,        heteroaryl, heteroarylalkenyl, heteroarylalkyl, heterocycle,        heterocyclealkenyl, heterocyclealkyi, hydroxyalkylcarbonyl,        nitroalkyl, R_(c)R_(d)N—, R_(p)O—, R_(p)Oalkyl- R_(c)Nalkyl-,        R_(c)R_(d)NC(O)alkyl-, R_(c)SO₂—, R_(c)SO₂alkyl-, R_(c)C(O)—,        R_(c)C)O)alkyl-, R_(c)OC(O)—, R_(c)OC(O)alkyl-,        R_(c)R_(d)NalkylC(O)—), R_(c)R_(d)NC(O)—,        R_(c)R_(d)NC(O)Oalkyl-, and R_(c)R_(d)NC(O)N(R_(c))alkyl-,        wherein R_(a) and R_(b) are each independently optionally        substituted at each occurrence with at least 1 or 2 substituents        each of which is independently selected from the group        consisting of alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro,        haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl,        heteroarylalkyl, alkoxyalkoxyalkyl, -(alkyl)(OR_(c)),        -(alkyl)(NR_(c)R_(d)), —SR_(c), —S(O)R_(c), —S(O)₂R_(c),        —OR_(c), —N(R_(c))(R_(d)), —C(O)R_(c), —C(O)OR_(c) and        —C(O)NR_(c)R_(d);    -   alternatively, R_(a) and R_(b), together with the nitrogen atom        to which they are attached, form a three- to six-membered ring        selected from the group consisting of heteroaryl and        heterocycle, wherein the heteroaryl and heterocycle are each        independently optionally substituted at each occurrence with at        least 1, 2 or 3 substituents each of which is independently        selected from the group consisting of alkyl, alkenyl, alkynyl,        oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl,        heteroaryl, heterocycle, arylalkyl, heteroarylalkyl,        alkoxyalkoxyalkyl, -(alkyl)(OR_(c)), -(alky(NR_(c)R_(d)),        -alkylSO₂NR_(c)R_(d), -alkylC(O)NR_(c)R_(d), —SR_(c),        —S(O)R_(c), —S(O)₂R_(c), —OR_(c), —N(R_(c))(R_(d)), —C(O)R_(c),        —C(O)OR_(c) and —C(O)NR_(c)R_(d);    -   R_(c) and R_(d) are each independently selected at each        occurrence from the group consisting of hydrogen, —NR_(f)R_(h),        —OR_(f), —CO(R_(f)), —SR_(f), —SOR_(f), —SO₂R_(f),        —C(O)NR_(f)R_(h), —SO₂NR_(f)R_(h), —C(O)OR_(f), alkenyl, alkyl,        alkynyl, cycloalkyl, cycloalkylalkyi, cycloalkenyl,        cycloalkenylalkyl, aryl, arylalkyl, haloalkyl, heteroaryl,        heteroarylalkyl, heterocycle and heterocyclealkyl; wherein each        R_(c) and R_(d) is independently optionally substituted at each        occurrence with at least 1, 2, or 3 substituents each of which        is independently selected from the group consisting of alkyl,        alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl,        haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl,        heteroarylalkyl, alkoxyalkoxyalkyl, -(alkyl)(OR_(f)),        -(alkyl)(NR_(f)R_(h)), —SR_(f), —S(O)R_(f), —SO₂R_(f), —OR_(f),        —N(R_(f))(R_(h)), —C(O)R_(f), —C(O)OR_(f), —C(O)NR_(f)R_(h),        —C(O)N(H)NR_(f)R_(h), —N(R_(c))C(O)OR_(f),        —N(R_(c))SO₂NR_(f)R_(h), —N(R_(c))C(O)NR_(f)R_(h),        -alkylN(R_(c))C(O)OR_(f), -alkylN(R_(c))SO₂NR_(f)R_(h), and        -alkylN(R_(c))C(O)NR_(f)R_(h);    -   alternatively, R_(c) and R_(d), together with the nitrogen atom        to which they are attached, form a three- to six-membered ring        selected from the group consisting of heteroaryl and        heterocycle, wherein the heteroaryl and heterocycle are each        independently optionally substituted at each occurrence with at        least 1, 2 or 3 substituents each of which is independently        selected from the group consisting of alkyl, alkenyl, alkynyl,        oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl,        heteroaryl, heterocycle, arylalkyl, heteroarylalkyl,        alkoxyalkoxyalkyl, -(alkyl)(OR_(f)), -(alkyl)(NR_(f)R_(h)),        —SR_(f), —S(O)R_(f), —S(O)₂R_(f), —OR_(f), —N(R_(f))(R_(h),        —C(O)R_(f), —C(O)OR_(f) and —C(O)NR_(f)R_(h);    -   R_(c) is selected from the group consisting of hydrogen,        alkenyl, alkyl and cycloalkyl;    -   R₁ and R_(h) are each independently selected at each occurrence        from the group consisting of hydrogen, alkyl, alkenyl, aryl,        arylalkyl, cycloalkyl, cycloalkylalkyi, cycloalkenyl,        cycloalkenylalkyl, heterocycle, heterocyclealkyl, heteroaryl and        heteroarylalkyl; wherein each R_(f) and R_(h) is independently        optionally substituted at each occurrence with at least 1, 2 or        3 substituents each of which is independently selected from the        group consisting of alkyl, alkenyl, alkynyl, cyano, halo, oxo,        nitro, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heterocycle,        heteroaryl, heteroarylalkyl, —OH, —O(alkyl), —NH₂, —N(H)(alkyl),        —N(alkyl)₂, —S(alkyl), —S(O)(alkyl), —SO₂alkyl, -alkyl—OH,        -alkyl-O-alkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,        -alkylS(alkyl), -alkylS(O)(alkyl), -alkylSO₂alkyl, —N(H)C(O)NH₂,        —C(O)OH, —C(O)O(alkyl), —C(O)alkyl, —C(O)NH₂, —C(O)NH₂,        —C(O)N(H)(alkyl), and —C(O)N(alkyl)₂;    -   alternatively, R_(f) and R_(h) together with the nitrogen atom        to which they are attached, form a three- to seven-membered ring        selected from the group consisting of heterocycle and        heteroaryl; wherein the heterocycle and heteroaryl are each        independently optionally substituted at each occurrence with at        least 1, 2 or 3 substituents each of which is independently        selected from the group consisting of alkyl, alkenyl, alkynyl,        cyano, halo, oxo, nitro, aryl, arylalkyl, cycloalkyl,        cycloalkenyl, heterocycle, heteroaryl, heteroarylalkyl, —OH,        —O(alkyl), —NH₂, —N(H)(alkyl), —N(alkyl)₂, —S(alkyl), —S(alkyl),        —S(O)(alkyl), -alkyl—OH, -alkyl-O-alkyl, -alkylNH₂,        -alkylN(H)(alkyl), -alkylS(alkyl), -alkylS(O)(alkyl),        -alkylSO₂alkyl, -alkylN(alkyl)₂, —N(H)C(O)NH₂, —C(O)OH,        —C(O)(alkyl), —C(O)alkyl, —C(O)NH₂, —C(O)NH₂, —C(O)N(H)(alkyl),        and —C(O)N(alkyl)₂;    -   R_(k) is independently selected at each occurrence from the        group consisting of hydrogen, alkenyl, alkyl, aryl, arylalkyl,        cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl,        cycioalkylalkyl, formylalkyl, haloalkyl, heteroaryl,        heteroarylalkyl, heterocycle, heterocyclealkyi, nitroalkyl,        R_(a)R_(b)Nalkyl-, R_(a)Oalkyl-, R_(a)R_(b)NC(O)—,        R_(a)R_(b)NC(O)alkyl, R_(a)S—, R_(a)S(O)—, R_(a)SO₂—,        R_(a)Salkyl-, R_(a)(O)Salkyl-, R_(a)SO₂alkyl-, R_(a)OC(O)—,        R_(a)OC(O)alkyl-, R_(a)C(O)— and R_(a)C(O)alkyl-, wherein each        R_(k) is independently optionally substituted at each occurrence        with at least 1, 2, or 3 substituents each of which is        independently selected from the group consisting of alkyl,        alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl,        haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl,        heteroarylalkyl, alkoxyalkoxyalkyl, -(alkyl)(OR_(c)),        -(alkyl)(NR_(c)R_(d)), —SR_(c), —S(O)R_(c), —S(O)₂R_(c),        —OR_(c), —N(R_(c))(R_(d)), —C(O)R_(c), —C(O)OR_(c) and        —C(O)NR_(c)R_(d);    -   R_(p) is independently selected at each occurrence from the        group consisting of hydrogen, alkenyl, alkyl, aryl, arylalkyl,        cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl,        cycioalkylalkyl, formylalkyl, haloalkyl, heteroaryl,        heteroarylalkyl, heterocycle, heterocyclealkyl, and nitroalkyl,        wherein each Rs, is independently optionally substituted at each        occurrence with at least 1, 2, or 3 substituents each of which        is independently selected from the group consisting of alkyl,        alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl,        haloaikoxy, aryl, heteroaryl, heterocycle, arylalkyl,        heteroarylalkyl, alkoxyalkoxyalkyl, -(alkyl)(OR_(c)),        -(alkyl)(NR_(c)R_(d)), —SR_(c), —S(O)R_(c), —S(O)₂R_(c),        —OR_(c), —N(R_(c))(R_(d)), —C(O)R_(c), —C(O)OR_(c) and        —C(O)NR_(c)R_(d); and    -   m is 0, 1, 2, 3, or 4.

A non-limiting example of a compound of this embodiment isN-[(3-{1-[(cyclobutyl)amino]-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-yl}-1,1-dioxo-1,4-dihydro-1λ⁶-thieno[2,3-e][1,2,4]thiadiazin -7-yl)methyl]methanesulfonamide (compound I). As demonstratedbelow, compound I showed an unexpectedly improved pharmacokineticprofile as compared to compounds such asN-[(3-{1-[(cyclopropylmethyl)amino]-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl}-1,1-dioxido-4H-thieno [2,3-e][1,2,4]thiadiazin-7-yl)methyl]methanesulfonamide(hereinafter “compound II”) andN-{3-[1-(cyclobutylamino)-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl]-1,1-dioxido-4H-1,2,4-benzothiadiazin -7-yl}methanesulfonamide (hereinafter “compoundIII”), where R¹ and R⁵ are not cyclobutyl-N(R_(a))- andR_(a)SO₂N(R_(f))alkyl-, respectively, and in particular, R¹ and R⁵ arenot cyclobutyl-N(H)— and CH₃SO₂N(H)-CH₂—, respectively.

Compound I also exhibited an unexpectedly high potency in the inhibitionof HCV RNA polymerase and HCV replication when compared to compoundssuch as 1-Benzyl-4-hydroxy-3-[7-(hydroxymethyl) 1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-3-yl]quinolin-2(1 H)-one, where R⁵ isnot R_(a)SO₂N(R_(f))alkyl- (e.g., CH₃SO₂N(H)—CH₂—). For instance,compound I exhibited about 100-fold higher potency in the inhibition ofHCV replication as compared to1-Benzyl-4-hydroxy-3-[7-(hydroxymethyl)-1,1-dioxido -4H-thieno[2,3-e][1,2,4]thiadiazin-3-yl]quinolin-2(1 H)-one.

The present invention also features pure or substantially pure compound1, or a pure or substantially pure pharmaceutically acceptable salt,stereoisomer or tautomer of compound I. As used herein, the term“substantially pure,” when used in reference to a compound, refers to apreparation or composition where the preparation/composition containsmore than 90% by weight of the compound, preferably more than 95% byweight of the compound, and more preferably more than 97% by weight ofthe compound

The present invention further features pharmaceutical compositionscomprising the compounds of the present invention or pharmaceuticallyacceptable salts thereof, and a pharmaceutically acceptable carrier.Each pharmaceutical composition of the invention can include 1, 2, 3 ormore compounds of the invention, or their respective pharmaceuticallyacceptable salts. Any compound described herein can be included in apharmaceutical composition of the present invention, e.g., a compoundhaving formula I or II.

In one embodiment, a pharmaceutical composition of the present inventioncomprises compound I or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable carrier. In another embodiment, apharmaceutical composition of the present invention comprises compound Ior a pharmaceutically acceptable salt thereof, at least another compoundof the present invention or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable carrier.

A pharmaceutical composition of the present invention can furthercomprise one or more other therapeutic agents, Non-limiting examples ofsuitable therapeutic agents include immune modulators (such asinterferon-alpha, pegylated-interferon-alpha, interferon-beta,interferon-gamma, cytokine, and vaccine (e.g., vaccine comprising anantigen and an adjuvant)), or antiviral agents (such as anti-HCV agentswhich inhibit the replication of HCV by inhibiting host cellularfunctions associated with viral replication or by targeting proteins ofthe viral genome, anti-HCV agents which treat or alleviate symptoms ofHCV infection including cirrhosis and inflammation of liver, anti-HBVagents which treat patients for disease caused by hepatitis B (HBV)infection (e.g., L-deoxythymidine, adefovir, lamivudine, or tenfovir),and anti-HIV agent which treat patients for disease caused by humanimmunodeficiency virus (HIV) infection (e.g., ritonavir, lopinavir,indinavir, nelfinavir, saquinavir, amprenavir, atazanavir, tipranavir,TMC-114, fosamprenavir, zidovudine, lamivudine, didanosine, stavudine,tenofovir, zalcitabine, abacavir, efavirenz, nevirapine, delavirdine,TMC-125, L-870812, S-1360, enfuvirtide (T-20), and T-1249)). As anon-limiting example, a pharmaceutical composition of the presentinvention can comprise compound I or a pharmaceutically acceptable saltthereof, and one or more other therapeutic agents described above.

In one embodiment, a pharmaceutical composition of the present inventioncomprises a compound of the present invention (e.g., compound 1) or apharmaceutically acceptable salt thereof, and one or more HCV proteaseinhibitors. Non-limiting examples of suitable HCV protease inhibitorsinclude

(hereinafter compound VX-950, Vertex Pharmaceuticals Inc.),

(hereinafter compound SCH503034, Schering-Plough Co.), andpharmaceutically acceptable salts thereof.

In another embodiment, a pharmaceutical composition of the inventioncomprises a compound of the present invention (e.g., compound I) or apharmaceutically acceptable salt thereof, and one or more additional HCVpolymerase inhibitors These additional polymerase inhibitors can benucleoside or non-nucleoside inhibitors, such as

(hereinafter compound NM283, Idenix Pharmaceuticals, Inc.).

In still another embodiment, a pharmaceutical composition of theinvention comprises a compound of the present invention (e.g., compoundI) or a pharmaceutically acceptable salt thereof, and one or more HCVreplication or translation inhibitors. Examples of these inhibitorsinclude, but are not limited to, IRES inhibitors, antisense RNA, orsiRNA

In yet another embodiment, a pharmaceutical composition of the inventioncomprises a compound of the present invention (e.g., compound I) or apharmaceutically acceptable salt thereof, and interferon. Non-limitingexamples of interferons suitable for this purpose include interferonalpha 2a, interferon alpha 2b, consensus interferon alpha, and pegylatedinterferon In many instances, a pharmaceutical composition of thisembodiment also includes1-(β-D-ribofuranosyl)-1H-1,2,4-triazole-3-carboxamide (ribavirin).

In one example, a pharmaceutical composition of the present inventioncomprises compound I or a pharmaceutically acceptable salt thereof, andcompound VX-950 or a pharmaceutically acceptable salt thereof. Inanother example, a pharmaceutical composition of the present inventioncomprises compound I or a or a pharmaceutically acceptable salt thereof,and compound SCH503034 or a pharmaceutically acceptable salt thereof.

The present invention further features methods of using the compounds orcompositions of the present invention to treat or prevent infectioncaused by an RNA-containing virus (e.g., HCV). In one embodiment, thesemethods comprise administering to a patient in need of such treatment atherapeutically effective amount of a pharmaceutical composition of thepresent invention, thereby treating or preventing infection of theRNA-containing virus (e.g., HCV) in the patient. Any pharmaceuticalcomposition described herein can be used for this purpose.

In another embodiment, these methods comprise administering to a patientin need of such treatment a therapeutically effective amount of acompound of the present invention or a pharmaceutically acceptable saltthereof, thereby treating or preventing infection of the RNA-containingvirus (e.g., HCV) in the patient In one example, the methods compriseadministering to a patient in need of such treatment a therapeuticallyeffective amount of compound I or a pharmaceutically acceptable saltthereof, thereby treating or preventing infection of the RNA-containingvirus (e.g., HCV) in the patient.

In still another embodiment, the methods comprise administering to apatient in need of such treatment a therapeutically effective amount oftwo or more compounds of the present invention or pharmaceuticallyacceptable salts thereof (e.g., compound I and another compound of thepresent invention, or pharmaceutically acceptable salts thereof),thereby treating or preventing infection of the RNA-containing virus(eg., HCV) in the patient.

In yet another embodiment, the methods comprise administering to apatient in need of such treatment a therapeutically effective amount ofone or more compounds of the present invention (or pharmaceuticallyacceptable salt or salts thereof) and one or more other therapeuticagents, thereby treating or preventing infection of the RNA-containingvirus (e.g., HCV) in the patient. Each of the other therapeutic agentscan be independently selected from immune modulators (such asinterferon-alpha, pegylated-interferon-alpha, interferon-beta,interferon-gamma, cytokine, and vaccine (e.g., vaccine comprising anantigen and an adjuvant)), or antiviral agents (such as anti-HCV agentswhich inhibit the replication of HCV by inhibiting host cellularfunctions associated with viral replication or by targeting proteins ofthe viral genome, anti-HCV agents which treat or alleviate symptoms ofHCV infection including cirrhosis and inflammation of liver, anti-HBVagents which treat patients for disease caused by hepatitis B (HBV)infection (e.g., L-deoxythymidine, adefovir, lamivudine, or tenfovir),and anti-HfV agents which treat patients for disease caused by humanimmunodeficiency virus (HIV) infection (e.g., ritonavir, lopinavir,indinavir, nelfinavir, saquinavir, amprenavir, atazanavir, tipranavir,TMC-114, fosamprenavir, zidovudine, lamivudine, didanosine, stavudine,tenofovir, zalcitabine, abacavir, efavirenz, nevirapine, delavirdine,TMC-125, L-870812, S-1360, enfuvirtide (T-20), or T-1249)). A compoundof the present invention and another therapeutic agent can beadministered to a patient in need thereof either simultaneously orsequentially.

In one example, a method of the present invention comprisesadministering a therapeutically effective amount of compound I (or apharmaceutically acceptable salt thereof) and an HCV protease inhibitorto a patient in need thereof, thereby treating or preventing HCVinfection in the patient. Non-limiting examples of HCV proteaseinhibitors suitable for this purpose include compound VX-950, compoundSCH503034, and pharmaceutically acceptable salts thereof.

In another example, a method of the present invention comprisesadministering a therapeutically effective amount of compound I (or apharmaceutically acceptable salt thereof) and another HCV polymeraseinhibitor to a patient in need thereof, thereby treating or preventingHCV infection in the patient. Non-limiting polymerase inhibitorssuitable for this purpose include nucleoside or non-nucleosideinhibitors.

In yet another example, a method of the present invention comprisesadministering a therapeutically effective amount of compound I (or apharmaceutically acceptable salt thereof) and an HCV replication ortranslation inhibitor to a patient in need thereof, thereby treating orpreventing HCV infection in the patient. Non-limiting examples of HCVreplication/translation inhibitors suitable for this purpose include,but are not limited to, IRES inhibitors, antisense RNA, or siRNA,

In still yet another example, a method of the present inventioncomprises administering a therapeutically effective amount of compound I(or a pharmaceutically acceptable salt thereof) and interferon (e.g.,interferon alpha 2a, interferon alpha 2b, consensus interferon alpha, orpegylated interferon) to a patient in need thereof, thereby treating orpreventing HCV infection in the patient.

In a further example, a method of the present invention comprisesadministering a therapeutically effective amount of compound I (or apharmaceutically acceptable salt thereof), interferon (e.g., interferonalpha 2a, interferon alpha 2b, consensus interferon alpha, or pegylatedinterferon), and 1-(β-D-ribofuranosyl)-1H-1,2,4-triazole-3-carboxamide(ribavirin) to a patient in need thereof, thereby treating or preventingHCV infection in the patient.

The present invention also features methods of inhibiting thereplication of an RNA-containing virus (e.g., HCV). The methods comprisecontacting the virus, or cells infected by the virus, with an effectiveamount of a compound of the present invention or a pharmaceuticallyacceptable salty thereof, thereby inhibiting the replication of thevirus. In one embodiment, the methods comprise contacting HCV virus withan effective amount of compound I or a pharmaceutically acceptable saltthereof, thereby inhibiting the replication of the virus. In anotherembodiment, the methods comprise contacting cells infected by HCV viruswith an effective amount of compound I or a pharmaceutically acceptablesalt thereof, thereby inhibiting the replication of the virus in thecells. In yet another embodiment, the methods comprise contacting HCVvirus with an effective amount of two or more compounds of the presentinvention or pharmaceutically acceptable salts thereof (e.g., compound Iand at least another compound of the present invention, orpharmaceutically acceptable salts thereof), thereby inhibiting thereplication of the virus. In still yet another embodiment, the methodscomprise contacting cells infected by HCV virus with an effective amountof two or more compounds of the present invention or pharmaceuticallyacceptable salts thereof (e.g., compound I and at least another compoundof the present invention, or pharmaceutically acceptable salts thereof),thereby inhibiting the replication of the virus in the cells. In stillanother embodiment, the methods comprise contacting HCV virus with aneffective amount of compound I and an HCV protease inhibitor (e.g.,VX-950 or SCH503034), thereby inhibiting the replication of the virus,In yet another embodiment, the methods comprise contacting cellsinfected by HCV virus with an effective amount of compound I and an HCVprotease inhibitor (e.g , VX-950 or SCH503034), thereby inhibiting thereplication of the virus in the cells In a further embodiment, themethods comprise contacting HCV virus with an effective amount ofcompound I and another HCV polymerase inhibitor (e.g., a nucleoside ornon-nucleoside inhibitor), thereby inhibiting the replication of thevirus. In another embodiment, the methods comprise contacting cellsinfected by HCV virus with an effective amount of compound I and anotherHCV polymerase inhibitor (e.g., a nucleoside or non-nucleosideinhibitor), thereby inhibiting the replication of the virus in thecells. In still another embodiment, the methods comprise contacting HCVvirus with an effective amount of compound I and an HCV replication ortranslation inhibitor (e.g., IRES inhibitors, antisense RNA, or siRNA),thereby inhibiting the replication of the virus. In still yet anotherembodiment, the methods comprise contacting cells infected by HCV viruswith an effective amount of compound I and an HCV replication ortranslation inhibitor (e.g., IRES inhibitors, antisense RNA, or siRNA),thereby inhibiting the replication of the virus in the cells. In anotherembodiment, the methods comprise contacting HCV virus with an effectiveamount of compound I and interferon (e.g., interferon alpha 2a,interferon alpha 2b, consensus interferon alpha, or pegylatedinterferon), thereby inhibiting the replication of the virus. In stillanother embodiment, the methods comprise contacting cells infected byHCV virus with an effective amount of compound I and interferon (e.g.,interferon alpha 2a, interferon alpha 2b, consensus interferon alpha, orpegylated interferon), thereby inhibiting the replication of the virusin the cells. In yet another embodiment, the methods comprise contactingHCV virus with an effective amount of compound I, interferon, and1-(β-D-ribofuranosyl)-1H-1,2,4-triazole-3-carboxamide (ribavirin),thereby inhibiting the replication of the virus. In still a furtherembodiment, the methods comprise contacting cells infected by HCV viruswith an effective amount of compound I, interferon, and1(β-D-ribofuranosyl)-1H-1,2,4-triazole-3-carboxamide (ribavirin),thereby inhibiting the replication of the virus in the cells.

As used herein, “inhibiting” means abolishing or significantly reducingthe original activity For instance, a compound of the present inventioninhibits the replication of HCV if the compound can reduce the level oractivity of HCV replication by at least 10%, 20%, 30%, 40%, 50%, 60%,70%, 80%, 90%, 95% or more.

The present invention also features methods of inhibiting HCV RNApolymerase. The methods comprise contacting HCV RNA polymerase with aneffective amount of a compound of the present invention or apharmaceutically acceptable salty thereof, thereby inhibiting theactivity of the HCV RNA polymerase. In one embodiment, the methodscomprise contacting HCV RNA polymerase with an effective amount ofcompound I or a pharmaceutically acceptable salt thereof, therebyinhibiting the activity of the HCV RNA polymerase. In anotherembodiment, the methods comprise contacting HCV RNA polymerase with aneffective amount of two or more compounds of the present invention orpharmaceutically acceptable salts thereof (e.g., compound I and at leastanother compound of the present invention, or pharmaceuticallyacceptable salts thereof), thereby inhibiting the activity of the HCVRNA polymerase.

The present invention further features use of a compound of the presentinvention, or a pharmaceutically acceptable salt thereof, to prepare amedicament for treating or preventing infection caused by anRNA-containing virus (e.g., HCV) in a patient. In one embodiment, thepresent invention provides the use of compound I or a pharmaceuticallyacceptable salt thereof, to prepare a medicament for treating orpreventing HCV infection. In another embodiment, the present inventionprovides the use of compound I and at least another compound of thepresent invention, or pharmaceutically acceptable salts thereof, toprepare a medicament for treating or preventing HCV infection.

In still another embodiment, the present invention provides the use ofone or more compounds of the present invention or pharmaceuticallyacceptable salt(s) thereof, and one or more other therapeutic agents, toprepare a medicament for treating or preventing viral infection (e.g.,HCV infection). In many examples, the compound(s) employed in thisembodiment includes compound I, and each of the other therapeutic agentsis independently selected from immune modulators (such asinterferon-alpha, pegylated-interferon-alpha, interferon-beta,interferon-gamma, cytokine, or vaccine (e.g., vaccine comprising anantigen and an adjuvant)), or antiviral agents (such as anti-HCV agentswhich inhibit the replication of HCV by inhibiting host cellularfunctions associated with viral replication or by targeting proteins ofthe viral genome, anti-HCV agent which treat or alleviate symptoms ofHCV infection including cirrhosis and inflammation of liver, anti-HBVagents which treat patients for disease caused by hepatitis B (HBV)infection (e.g., L-deoxythymidine, adefovir, lamivudine, or tenfovir),or anti-HIV agents which treat patients for disease caused by humanimmunodeficiency virus (HIV) infection (e.g., ritonavir, lopinavir,indinavir, neifinavir, saquinavir, amprenavir, atazanavir, tipranavir,TMC-114, fosamprenavir, zidovudine, lamivudine, didanosine, stavudine,tenofovir, zalcitabine, abacavir, efavirenz, nevirapine, delavirdine,TMC-125, L-870812, S-1360, enfuvirtide (T-20), or T-1249)).

In one example, the present invention provides the use of compound I (ora pharmaceutically acceptable salt thereof) and an HCV proteaseinhibitor, to prepare a medicament for treating or preventing HCVinfection. Non-limiting examples of HCV protease inhibitors suitable forthis purpose include compound VX-950, compound SCH503034, andpharmaceutically acceptable salts thereof

In another example, the present invention provides the use of compound I(or a pharmaceutically acceptable salt thereof) and another HCVpolymerase inhibitor, to prepare a medicament for treating or preventingHCV infection. Non-limiting polymerase inhibitors suitable for thispurpose include nucleoside or non-nucleoside inhibitors.

In yet another example, the present invention provides the use ofcompound I (or a pharmaceutically acceptable salt thereof) and an HCVreplication or translation inhibitor, to prepare a medicament fortreating or preventing HCV infection. Non-limiting examples of HCVreplication/translation inhibitors suitable for this purpose include,but are not limited to, IRES inhibitors, antisense RNA, or siRNA.

In still yet another example, the present invention provides the use ofcompound I (or a pharmaceutically acceptable salt thereof) andinterferon, to prepare a medicament for treating or preventing HCVinfection. Non-limiting examples of interferon suitable for this purposeinclude interferon alpha 2a, interferon alpha 2b, consensus interferonalpha, and pegylated interferon

In a further example, the present invention provides the use of compoundI (or a pharmaceutically acceptable salt thereof), interferon and1-(β-D-ribofuranosyl)-1H-1,2,4-triazole-3-carboxamide (ribavirin), toprepare a medicament for treating or preventing HCV infection.

The present invention also features processes for the preparation of thecompounds of the invention. In one embodiment, the present inventionprovides a process for preparing a compound of formula (I) as describedabove, which process comprises:

-   -   (a) contacting a compound of formula (26)

with carbon disulfide and a methylating agent in the presence of a baseto provide a compound of formula (27)

-   -   (b) contacting the compound of formula (27) with a compound of        formula (13)

wherein A, R¹, R², R³, and R⁵ are as defined above.

In another embodiment, the present invention provides another processfor preparing a compound of formula (I), which process comprises:

-   -   (a) contacting a compound of formula (26)

with tris(methylthio)methyl methyl sulfate or tris(methylthio)methylmethyl tetrafluoroborate in the presence of a base to provide a compoundof formula (27)

-   -   (b) contacting the compound of formula (27) with a compound of        formula (13)

wherein A, R¹, R², R³, R⁵ and n are as defined above.

In some embodiments of the above processes, the compound of formula (13)is 2-amino -4-(methanesulfonyl-amino-methyl)-thiophene-3-sulfonic acidamide:

In another embodiment, the present invention provides a process forpreparing a compound of formula (13A). The process comprises:

-   -   (a) reacting compound of formula (A) with an agent selected from        the group consisting of (1) isopropyl magnesium chloride, (2)        isopropyl magnesium bromide, and (3) magnesium metal to obtain a        compound of formula (B) in which X is selected from the group        consisting of chloro and bromo:

-   -   (b) reacting the compound of formula (B) with        4-methylbenzenesulfonyl cyanide (also known as TsCN or TosCN) or        ClC(O)O-alkyl to obtain a compound of formula (C) in which E is        CN or C(O)O-alkyl (depending on whether TosCN or C(O)O-alkyl is        used):

In some embodiments of the process for preparing compound of formula(13A), compound (C) is prepared as described in Example 2A (Part A), Inother embodiments, compound (C) is prepared as described in Example 2B(Part A).

The compounds of the invention can comprise asymmetrically substitutedcarbon atoms, As a result, all stereoisomers of the compounds of theinvention are meant to be included in the invention, including racemicmixtures, mixtures of diastereomers, mixtures of enantiomers, as well asindividual optical isomers, including, enantiomers and singlediastereomers of the compounds of the invention substantially free fromother enantiomers or diastereomers. By “substantially free” is meantgreater than about 80% free of other enantiomers or diastereomers of thecompound, more preferably greater than about 90% free of otherenantiomers or diastereomers of the compound, even more preferablygreater than about 95% free of other enantiomers or diastereomers of thecompound, even more highly preferably greater than about 98% free ofother enantiomers or diastereomers of the compound and most preferablygreater than about 99% free of other enantiomers or diastereomers of thecompound.

In addition, compounds comprising the possible geometric isomers ofcarbon-carbon double bonds and carbon-nitrogen double are also meant tobe included in this invention.

Individual stereoisomers of the compounds of this invention can beprepared by any suitable methods as appreciated by one of ordinary skillin the art. These methods include stereospecific synthesis,chromatographic separation of diastereomers, chromatographic resolutionof enantiomers, conversion of enantiomers in an enantiomeric mixture todiastereomers and then chromatographically separating the diastereomersand regeneration of the individual enantiomers, enzymatic resolution andthe like.

Stereospecific synthesis involves the use of appropriate chiral startingmaterials and synthetic reactions, which do not cause racemization, orinversion of stereochemistry at the chiral centers.

Diastereomeric mixtures of compounds resulting from a synthetic reactioncan often be separated by chromatographic techniques that are well knownto those of ordinary skill in the art

Chromatographic resolution of enantiomers can be accomplished on chiralchromatography resins. Chromatography columns containing chiral resinsare commercially available. In practice, the racemate may be placed insolution and loaded onto the column containing the chiral stationaryphase. The enantiomers are then separated by HPLC.

Resolution of enantiomers can also be accomplished by converting theenantiomers in the mixture to diastereomers by reaction with chiralauxiliaries. The resulting diastereomers can then be separated by columnchromatography. This technique is especially useful when the compoundsto be separated contain a carboxyl, amino or hydroxyl group that willform a salt or covalent bond with the chiral auxiliary. Chirally pureamino acids, organic carboxylic acids or organosulfonic acids areespecially useful as chiral auxiliaries. Once the diastereomers havebeen separated by chromatography, the individual enantiomers can beregenerated. Frequently, the chiral auxiliary can be recovered and usedagain.

Enzymes, such as esterases, phosphatases and lipases, can be useful forresolution of derivatives of the enantiomers in an enantiomeric mixture.For example, an ester derivative of a carboxyl group in the compounds tobe separated can be prepared. Certain enzymes will selectively hydrolyzeonly one of the enantiomers in the mixture. Then the resultingenantiomerically pure acid can be separated from the unhydrolyzed ester.

The present compounds may exhibit the phenomena of tautomerism orstructural isomerism. As the drawings/formulas within this specificationcan only represent one possible tautomeric or structural isomeric form,it should be understood that the invention encompasses any tautomeric orstructural isomeric form, or mixtures thereof, which possess the abilityto inhibit hepatitis C, and is not limited to any one tautomeric orstructural isomeric form utilized within the drawings/formulas.

In addition, solvates and hydrates of the compounds of the invention aremeant to be included in this invention

When any variable (for example R¹, R², R³, m, n, etc ) occurs more thanone time in a substituent, compound or formula described herein, itsdefinition on each occurrence is independent of its definition at everyother occurrence. In addition, combinations of substituents arepermissible if such combinations result in stable compounds Stablecompounds can be isolated in a useful degree of purity from a reactionmixture.

The compounds of the present invention can exist as pharmaceuticallyacceptable salts. The term “pharmaceutically acceptable salt,” as usedherein, represents acid or base salts or zwitterionic forms of thecompounds of the present invention which are water or oil-soluble ordispersible, which are suitable for treatment of diseases without unduetoxicity, irritation, and allergic response; which are commensurate witha reasonable benefit/risk ratio, and which are effective for theirintended use The salts can be prepared during the final isolation andpurification of the compounds or separately by reacting a basic group(for example, a nitrogen containing group) with a suitable acid.Representative acid addition salts include acetate, adipate, alginate,citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,camphorate, camphorsulfonate, digluconate, glycerophosphate,hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxy ethansulfonate, lactate, maleate,mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, pamoate, pectinate, persuifate,3-phenylproprionate, picrate, pivalate, propionate, succinate, tartrate,trichloroacetate, tifluoroacetate, phosphate, glutamate, bicarbonate,para-toluenesulfonate, and undecanoate. Also, amino groups in thecompounds of the present invention can be quaternized with methyl,ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl,diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, andsteryl chlorides, bromides, and iodides; and benzyl and phenethylbromides.

Basic addition salts can be prepared during the final isolation andpurification of the compounds by reacting an acidic group (for example,a carboxy group or an enol) with a suitable base such as the hydroxide,carbonate, or bicarbonate of a metal cation or with ammonia or anorganic primary, secondary, or tertiary amine The cations ofpharmaceutically acceptable salts include lithium, sodium, potassium,calcium, magnesium, and aluminum, as well as nontoxic quaternary aminecations such as ammonium, tetramethylammonium, tetraethylammonium,methylamine, dimethyiamine, trimethylamine, triethylamine, diethylamine,ethylamine, tributylamine, pyridine, N,N-dimethylaniline,N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine,dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, andN,N′-dibenzylethylenediamine. Other representative organic amines usefulfor the formation of basic addition salts include ethylenediamine,ethanolamine, diethanolamine, piperidine, and piperazine.

Preferred salts of the compounds of the present invention includemonosodium, disodium, triethylamine salt, trifluoroacetate andhydrochloride.

The present compounds can also exist as pharmaceutically acceptableprodrugs. The term “pharmaceutically acceptable prodrug,” refers tothose prodrugs or zwitterions which are suitable for use in contact withthe tissues of patients without undue toxicity, irritation, and allergicresponse, are commensurate with a reasonable benefitVrisk ratio, and areeffective for their intended use. “Prodrugs” are considered to becovalently bonded carriers, which release the active parent drug offormula I or II in vivo when such prodrugs are administered to amammalian subject. Prodrugs of the compounds of formula I or II(including but not limited to compound I) can be prepared by modifyingfunctional groups present in the compounds in such a way that themodifications can be cleaved either during routine manipulation or invivo. Prodrugs include compounds wherein hydroxy, amine, carboxy, orsulfhydryl groups are bonded to another group, which is cleavable whenadministered to a mammalian subject, thereby forming free hydroxyl,amino, carboxy, or sulfhydryl groups. Examples of prodrugs include, butare not limited to, acetate, formate, and benzoate derivatives of thehydroxy, carboxy and amine functional groups in the compounds of thepresent invention (e.g., the hydroxyl or amino groups in compound I).

A compound of the present invention can be administered alone or incombination with other antiviral or therapeutic agents. When using acompound, the specific pharmaceutically effective dose level for anyparticular patient will depend upon factors such as the disorder beingtreated and the severity of the disorder; the activity of the particularcompound used; the specific composition employed; the age, body weight,general health, sex, and diet of the patient; the time ofadministration; the route of administration; the rate of excretion ofthe compound employed; the duration of treatment; and drugs used incombination with or coincidently with the compound used. The compoundscan be administered orally, parenterally, osmotically (nasal sprays),rectally, vaginally, or topically in unit dosage formulations containingcarriers, adjuvants, diluents, vehicles, or combinations thereof. Theterm “parenteral” includes infusion as well as subcutaneous,intravenous, intramuscular, and intrasternal injection.

Parenterally administered aqueous or oleaginous suspensions of thecompounds can be formulated with dispersing, wetting, or suspendingagents. The injectable preparation can also be an injectable solution orsuspension in a diluent or solvent. Among the acceptable diluents orsolvents employed are water, saline, Ringer's solution, buffers,monoglycerides, or diglycerides.

Transdermal patches can provide controlled delivery of the compounds.The rate of absorption can be slowed by using rate-controlling membranesAbsorption enhancers can be used to increase absorption.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules, These solid dosage forms can optionallycomprise diluents such as sucrose, lactose, starch, talc, silicic acid,aluminum hydroxide, calcium silicates, polyamide powder, tabletinglubricants, and tableting aids such as magnesium stearate ormicrocrystalline cellulose. Capsules, tablets and pills can alsocomprise buffering agents, and tablets and pills can be prepared withenteric coatings or other release-controlling coatings Powders andsprays can also contain excipients such as talc, silicic acid, aluminumhydroxide, calcium silicate, polyamide powder, or mixtures thereofSprays can additionally contain customary propellants such aschlorofluorohydrocarbons or substitutes therefore.

Liquid dosage forms for oral administration include emulsions,microemulsions, solutions, suspensions, syrups, and elixirs comprisinginert diluents. These compositions can also comprise adjuvants such aswetting, emulsifying, suspending, sweetening, flavoring, and perfumingagents,

Topical dosage forms include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants, and transdermal patches. Thecompound is mixed under sterile conditions with a carrier and any neededpreservatives or buffers. These dosage forms can also include excipientssuch as cellulose derivatives, polyethylene glycols, silicones,bentonites, silicic acid, or mixtures thereof. Suppositories for rectalor vaginal administration can be prepared by mixing the compounds with asuitable non-irritating excipient such as cocoa butter or polyethyleneglycol, each of which is solid at ordinary temperature but fluid in therectum or vagina. Ophthalmic formulations comprising eye drops, eyeointments, powders, and solutions are also contemplated as being withinthe scope of this invention.

The compounds of the invention can inhibit HCV RNA-dependent RNApolymerase, an enzyme essential for HCV viral replication. They can beadministered as the sole active pharmaceutical agent, or used incombination with one or more other agents to treat hepatitis Cinfections or the symptoms associated with HCV infection. Other agentsto be administered in combination with a compound of the presentinvention include drugs that can suppress HCV viral replication bydirect or indirect mechanisms. These drugs include, but are not limitedto, host immune modulators, for example, interferon-alpha, pegylatedintei feion-alpha, CpG oligonucleotides and the like, or antiviralcompounds that inhibit host cellular functions such as inosinemonophosphate dehydrogenase, for example, ribavirin and the like. Alsoincluded are cytokines that modulate immune function Also included arevaccines comprising HCV antigens or antigen adjuvant combinationsdirected against HCV. Also included are agents that interact with hostcellular components to block viral protein synthesis by inhibiting theinternal ribosome entry site (IRES) initiated translation step of HCVviral replication or to block viral particle maturation and release withagents targeted toward the viroporin family of membrane proteins suchas, for example, HCV P7 and the like, Other agents to be administered incombination with a compound of the present invention include any agentor combination of agents that inhibit the replication of HCV bytargeting proteins of the viral genome involved in the viralreplication. These agents include but are not limited to otherinhibitors of HCV RNA-dependent RNA polymerase such as, for example,nucleoside type polymerase inhibitors described in WO0190121(A2), orU.S. Pat. No. 6,348,587B1 or WO0160315 or WO0132153 or non-nucleosideinhibitors such as, for example, benzimidazole polymerase inhibitorsdescribed in EP1162196A1 or WO0204425 or inhibitors of HCV protease suchas, for example, peptidomimetic type inhibitors such as BILN2061 and thelike or inhibitors of HCV helicase.

Other agents to be administered in combination with a compound of thepresent invention include any agent or combination of agents thatinhibit the replication of other viruses for co-infected individuals.These agent include but are not limited to therapies for disease causedby hepatitis B (HBV) infection such as, for example, adefovir,lamivudine, LdT (L-deoxythymidine) and tenofovir or therapies fordisease caused by human immunodeficiency virus (HIV) infection such as,for example, protease inhibitors: ritonavir, lopinavir, indinavir,nelfinavir, saquinavir, amprenavir, atazanavir, tipranavir, TMC-114,fosamprenavir; reverse transcriptase inhibitors: zidovudine, lamivudine,didanosine, stavudine, tenofovir, zalcitabine, abacavir, efavirenz,nevirapine, delavirdine, TMC-125; integrase inhibitors: L-870812,S-1360, or entry inhibitors: enfuvirtide (T-20), T-1249.

Other agents to be administered in combination with a compound of thepresent invention include any agent or combination of agents that treator alleviate symptoms of HCV infection including cirrhosis andinflammation of the liver.

When administered as a combination, the therapeutic agents can beformulated as separate compositions, which are given at the same time orwithin a predetermined period of time, or the therapeutic agents can begiven as a single unit dosage form.

The total daily dose of a compound administered to a host in single ordivided doses can be, without limitation, in the amount of from about0.001 to about 100 mg/kg body weight. Single dose compositions cancontain these amounts or submultiples thereof to make up the daily dose.

The biological activities of the compounds of the invention (e.g.,compound I) can be evaluated using the methods described in U.S. patentapplication Ser. No. 10/699,513, now U.S. patent application PublicationNo. 20040167123, which is incorporated herein by reference in itsentirety For instance, the 50% inhibitory concentration (IC₅₀) of an HCVpolymerase inhibitor can be evaluated according to the followingbiochemical HCV polymerase inhibition assays, Either two-fold serialdilutions (fractional inhibition assay) or a narrower range of dilutionsspanning the IC₅₀ (tight binding assay) of the inhibitors are incubatedwith 20 mM Tris—Cl pH 7.5, 5 mM MgCl₂, 50 mM NaCl, 1 mM dithiothreitol,1 mM ethylene diamine tetraacetic acid (EDTA), 300 μM GTP, and 150 to300 nM NS5B (HCV Strain 1B (J14, GenBank accession number AF054247, orH77, GenBank accession number AF011751)) for 15 minutes at roomtemperature, The reaction can be initiated by the addition of 20 μM CTP,20 μl ATP, 1 μM 3 H-UTP (10 mCi/μmol), 150 nM template RNA (see and 0.4U/μl RNase inhibitor (RNasin, Promega), and allowed to proceed for 2 to4 hours at room temperature. Reaction volume is 50 μl The reaction isterminated by the addition of 1 volume of 4 mM spermine in 10 mM Tris—ClpH 8.0, 1 mM EDTA. After incubation for at least 15 minutes at roomtemperature, the precipitated RNA is captured by filtering through aGF/B filter (Millipore) in a 96 well format. The filter plate is washedthree times with 200 μl each of 2 mM spermine, 10 mM Tris—Cl pH 8.0, 1mM EDTA, and 2 times with ethanol. After air drying, 30 μl of Microscint20 scintillation cocktail (Packard) is added to each well, and theretained cpm is determined by scintillation counting. IC₅₀ values arecalculated by a two-variable nonlinear regression equation using anuninhibited control and a fully inhibited control sample to determinethe minimum and maximum for the curve. Tight-binding assays areperformed on those compounds exhibiting IC₅₀ values less than 0.15 μM inthe fractional inhibition assay in order to more precisely measure theIC₅₀ values. Retained cpm are plotted vs. inhibitor concentration andfit to equation 1 using non-linear regression (Morrison and Stone,COMMENTS MOL. CELL. BlOPHYS., 2: 347-368 (1985)) to obtain the IC₅₀values.

Retainedcpm=A[sqrt{(IC₅₀+I_(t)−E_(t))²+4IC₅₀E_(t)}−(IC₅₀+I_(t)−E_(t))]  equationI

where A=V_(max)[S]/2(K_(m)+[S]); I_(t)=total inhibitor concentration andE_(t)=total active concentration of enzyme. The sequence of the templateRNA is identical to the sequence described in paragraph 847 of U.S.Patent Application Publication No. 20040167123.

The 50% inhibitory concentration of an HCV inhibitor (EC₅₀) can also beevaluated using HCV replicon assays as described in Ikeda et al., J.VIROL., 76: 2997-3006 (2002), and Blight et al, SCIENCE, 290:1972-1974(2000), with the following modifications. Replicon cells are plated at3×10³ cells per well in 96-well plate in DMEM medium containing 5% fetalcalf serum. At day 1, culture medium is removed and replaced with freshmedium containing eight serial 2-fold dilutions of the compound ofinterest. The final concentration of DMSO in medium is 0.5%, Theuntreated control culture is treated in an identical manner except noinhibitor is added to the medium. Plates are incubated in a CO₂incubator at 37° C. On Day 4, 100 μl lysis buffer (RTL) (Qiagen) isadded to each well after removal of culture medium. RNA is purifiedaccording to manufacturer's recommendations (Qiagen RNAeasy) and elutedin 200 μl of water. The HCV RNA level is quantified from a portion (5 μlout of 200 μ) of the purified RNA by real-time RT-PCR method. Theprimers and probe are derived from specific sequence in the 5′UTRregion. RT-PCR reaction is performed at 48° C. for 30 min, followed by40 cycles set to 95° C., 15 s; 54° C., 30 s; and 72° C., 40 s. Thepercentage reduction of HCV RNA in the presence of compound iscalculated and the 50% inhibitory concentration (EC50) is calculated bynon-linear regression analysis using the Prism program.

When tested using the biochemical HCV polymerase inhibition assays,representative compounds of the present invention (including compound I)inhibited HCV polymerase IB with the 50% inhibitory concentrations inthe range of from about 0.001 μM to about 50 μM. When tested using theHCV replicon assays, representative compounds of the present invention(including compound I) inhibited the replicon production with the 50%inhibitory concentrations in the range of from about 0.001 μM to about50 μM.

The compounds of the invention are named by ACD/ChemSketch version 5.0(developed by Advanced Chemistry Development, Inc., Toronto, ON, Canada)or are given names consistent with ACD nomenclature. As usedhereinbelow, DMF refers to N,N-dimethyiformamide, DMSO refers todimethylsulfoxide, and THF refers to tetrahydrofuran.

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic schemes, whichillustrate the methods by which the compounds of the invention may beprepared. Starting materials can be obtained from commercial sources orprepared by well-established literature methods known to those ofordinary skill in the art. The groups A, R¹, R², R³, R⁴, R⁵, and n areas defined above unless otherwise noted below.

This invention is intended to encompass compounds having formula (I)when prepared by synthetic processes or by metabolic processes.Preparation of the compounds of the invention by metabolic processesincludes those occurring in the human or animal body (in vivo) orprocesses occurring in vitro.

As shown in Scheme 1, compounds of formula (2) can be reacted withcompounds of formula (3) in the presence of phosphorous oxychforideunder heating conditions to provide compounds of formula (4). Compoundsof formula (4) can be reacted with a base such as sodium hydride,potassium hydride, lithium hexamethyldisiiazide, and the like in solventsuch as but not limited to dimethylacetamide, dimethylformamide, THF,and the like, followed by the addition of R¹-X, (wherein X is Br, Cl, I,CF₃S(O)₂—, CH₃S(O)₂—, or tosyl) to provide compounds of formula (5).

Alternatively, compounds of formula (6) can be treated with compounds offormula (7) under heating conditions optionally in the presence of abase such as potassium carbonate and a catalyst such as copper bromide,to provide compounds of formula (8). Compounds of formula (8) can betreated with reagents including but not limited to phosgene, diphosgene,triphosgene in solvents such as but not limited to 1,2-dichloroethane,carbon tetrachloride, 1,4-dioxane or mixtures thereof, under heatingconditions to provide compounds of formula (5).

In addition, compounds of formula (9) can also be reacted with reagentsincluding but not limited to phosgene, diphosgene, triphosgene,carbonyldiimidazole, ethyl chloroformate and the like in the presence ofa base such as potassium hydroxide, pyridine, lithium hydroxide, and thelike in solvents such as but not limited to water, toluene, benzene, andthe like under heating conditions to provide compounds of formula (5).

Compounds of formula (5) can be treated with compounds of formula (10)in the presence of a base such as sodium hydride, potassium hydride,lithium hexamethyldisilazide, and the like in a solvent such as but notlimited to THF, diethyl ether, methyl tert-butyl ether followed by thetreatment with an acid such as acetic acid, dichloroacetic acid orsulfuric acid to provide compounds of formula (11) which arerepresentative of a compound of formula (I), where R⁴ is hydroxy.

Compounds of formula (5) can be reacted with diethyl malonate that hasbeen pretreated with a base such as sodium hydride, potassium hydride,and the like in solvents such as dimethylacetamide, dimethylformamide,THF, and the like under heated conditions to provide compounds offormula (12). Compounds of formula (12) can be treated with compounds offormula (13) in solvents such as toluene, mesitylene, benzene, and thelike under heated conditions to provide compounds of formula (14).Compounds of formula (14) can be treated with a base such as sodiumhydroxide, potassium hydroxide, lithium hydroxide, and the like in waterunder heated conditions to provide compounds of formula (11).

Alternatively, compounds of formula (8) can be treated with ethylchloromalonate in the presence of a base such as triethylamine,diisopropylethylamine, pyridine, and the like in solvents such asdichloromethane, chloroform, carbon tetrachloride to provide compoundsof formula (15). Alternatively, compounds of the formula (8) can betreated with ethyl chloromalonate in solvents such as benzene, tolueneunder heating conditions to provide compounds of formula (15). Compoundsof formula (15) can be treated with sodium ethoxide in ethanoi toprovide compounds of formula (12).

Scheme 7 shows the preparation of compounds of formula (I) where R⁴ ishalo. Compounds of formula (11) can be treated with reagents known tothose skilled in the art, which are commonly used to convert alcohols tochlorides For example, compounds of formula (11) can be treated withreagents including but not limited to PCl₅, PCl₃, POCl₃, or thionylchloride, with or without solvents such as but not limited todichloromethane, chloroform and benzene, to provide compounds of formula(I) which are representative of compounds where R⁴ is chlorine. Similartransformations are possible using PBr₃ or DAST to convert the saidalcohol to the corresponding compound of formula (I) where R⁴ is bromideand fluoride, respectively. Alternatively, compound of formula (I)wherein R⁴ is iodo can be prepared by (a), reacting compound of formula(11) with a mesylating reagent such as methanesulfonyl chloride ormethanesulfonyl anhydride in the presence of an amine base such astriethylamine, pyridine or diisopropylethylamine in solvents such as butnot limited to dichloromethane, acetonitrile, carbon tetrachloride,chloroform, and (b) treatment of the mesylate thus formed withN-iodosuccinimide.

As shown in Scheme 8, compounds of formula (16) can be converted tocompounds of formula (17) which are representative of compounds offormula (I) where R⁴ is R_(a)R_(b)N-, by treatment with an amine havingthe formula R_(a)R_(b)NH, (where R_(a) and R_(b) are as definedhereinabove) in a polar solvent such as methanol, ethanol, and the like,under heating conditions to provide compounds of formula (17)

Compounds of formula (21) can be treated with aqueous base such as butnot limited to potassium hydroxide, sodium hydroxide and the like, toprovide compounds of formula (22) Compounds of formula (22) can betreated with a metal hydride base such as sodium hydride, anorganolithium reagent (e.g. 1-BuLi, n-BuLi, or s-BuLi), or lithiumhexamethyldisilazide in an appropriate solvent or a mixture of solventsselected from THF, DMSO, DMF, dioxane, ether, dichloromethane, and thelike, followed by the addition of RaX wherein X is Br, Cl, I, CF₃S(O)₂—,CH₃S(O)₂—, or tosyl to provide compounds of formula (23) which arerepresentative of compounds of formula (I) wherein R¹ is —NHRa.

Compounds of formula (12) can be reacted with aqueous base solutionssuch as potassium hydroxide and the like under heated conditions toprovide compounds of formula (26). Compounds of formula (26) can bereacted with a base in a solvent, or mixtures of solvents such as, butnot limited to, N,N-dimethyiformamide, tetrahydrofuran, diethyl ether,or methyl tert-butyl ether, and the like, followed by treatment withcarbon disulfide at a temperature of about room temperature to about 70°C. Examples of the base include, but not limited to, sodium hydride,potassium hydride, lithium diisopropylamide, sodium hexamethyldisilazideand lithium hexamethyldisilazide. Subsequent treatment with amethylating reagent at a temperature of about 25° C. provides compoundsof formula (27). Examples of the methylating agent include, but notlimited to, methyl iodide, methyl triflate, dimethylsulfate, and thelike,

Alternatively, compounds of the formula (26) can be reacted withtris(methylthto)methyl methyl sulfate in the presence of a base in asolvent such as 1,4-dioxane or dimethylacetamide, and the like, at atemperature of about 25° C. to about 150° C. to give compounds offormula (27). Examples of the base include, but are not limited to,organic amine bases such as imidazole, 1-methylimidazole,2-methylimidazole, 2-isopropylimidazole, 4-methylimidazole,4-nitroimidazole, pyridine, N,N-dimethylaminopyridine, 1,2,4-triazole,pyrrole, 3-methylpyrrole, triethylamine, diisopropylethylamine orN-methylmorpholine and the like,

Compounds of formula (27) can be treated with compounds such as (13) ina solvent or a mixture of solvents, such as but not limited to, toluene,benzene, dioxane or tetrahydrofuran, and the like, at a temperature ofabout 50° C. to about 150° C. to provide compounds of formula (11).

Compounds of the formula (29) wherein X is I, Br, CI or F can be treatedwith alkyl thiols such as benzene methyithiol in the presence of a basesuch as sodium carbonate in solvents such as ethanol and the like underheated conditions to give compounds of the formula (30). Treatment of(30) with chlorine gas in hydrochloric acid or acetic acid providescompounds of the formula (31). Compounds of the formula (31) in solventssuch as but not limited to dichloromethane, tetrahydrofuran or dioxanecan be treated with ammonia or ammonium hydroxide to give compounds ofthe formula (32). Reduction of compounds of the formula (32) with ironpowder and ammonium chloride in aqueous alcoholic solvents such asmethanol or ethanol under heated conditions optionally with iron powderin acetic acid under heated conditions to provide compounds of theformula (13).

Compounds of formula (42) can be sulfonylated with a sulfonyl chlorideof formula R_(n)SO₂Cl in the presence of a base such as pyridine aloneor an amine base such as triethylamine, diisopropylethylamine, and thelike in a solvent or combination of solvents such as dichloromethane,tetrahydrofuran, or dioxane, to provide compounds of formula (46),Alternatively, compounds of formula (42) can be sulfamoyiated in thepresence of an amine base such as but not limited to triethylamine, ordiisopropylethylamine, and the like, in a solvent or combination ofsolvents such as dichloromethane, tetrahydrofuran or dioxane, and thelike, with compounds of formula (49) to give compounds of formula (47)Compounds of formula (49) can be obtained by treating chlorosulfonylisocyanate and 2-chloroethanol in conditions that are well known in theart. Compounds of formula (47) can be treated further with an aminehaving the formula R_(a)R_(b)NH, (where R_(a) and R_(b) are as definedherein) in a solvent or combination of solvents such as dichloromethane,THF, or acetonitrile, and the like, under heating conditions to providecompounds of formula (48), Compounds of formula (42) can besulfamoylated in the presence of an amine base such as triethylamine, ordiisopropylethylamine, and the like, in a solvent or combination ofsolvents such as dichloromethane, tetrahydrofuran or dioxane, and thelike, with compounds of formula (54) to give compounds of formula (48).Compounds of formula (54) can be obtained by treating an amine of theformula R_(a)R_(b)NH with sulfuryl chloride or by (a) treating an amineof the formula R_(a)R_(b)NH with chlorosulfonic acid, and (b) contactingthe product of step (a) with a chlorinating agent such as phosphorouspentachloride and the like in conditions that are well known in the art.

Similarly, compounds of formula (11) wherein R⁵ is -alkylNH₂ can beconverted to compounds of formula (11) wherein R⁵ is-alkylNHSO₂NR_(a)R_(b) using the conditions for the transformation ofcompounds of formula (42) to compounds of formula (48). Compounds offormula (11) wherein R⁵ is -alkylNH₂ can be converted to compounds offormula (11) wherein R⁵ is -alkylNHSO₂R_(a) can be achieved by employingthe conditions for the transformation of compounds of formula (42) tocompounds of formula (46)

Compounds of formula (42) can be sulfamoylated with a sulfamoyl chlorideof formula R_(c)OC(O)NHSO₂Cl (50), in the presence of an amine base suchas pyridine, triethylamine or diisopropylethylamine, and the like, in asolvent or combination of solvents such as dichloromethane,tetrahydrofuran, diethyl ether, benzene, or acetonitrile, and the like,to provide compounds of formula (51). Compounds of formula (50) can beprepared by treating an alcohol of formula R_(e)OH with chlorosulfonylisocyanate in a solvent or combination of solvents such asdichloromethane, carbon tetrachloride, diethyl ether, benzene, ortoluene, and the like. Compounds of formula (51) can be treated furtherwith an alcohol having the formula R_(a)OH in the presence oftri-n-butylphosphine or triphenylphosphine, and the like, anddiisopropylazodicarboxylate, 1,1′-(azadicarbonyl)piperidine, ordiethylazodicarboxylate, and the like, in a solvent or combination ofsolvents such as dichloromethane or tetrahydrofuran to provide compoundsof formula (52). Alternatively, compounds of formula (52) wherein R_(a)is methyl can be obtained by methylating compounds of formula (51) witha methylating agent such as, but not limited to, methyl iodide, dimethylsulfate, trimethysiiyidiazomethane in conditions that are well known inthe art. Transformation of compounds of formula (52) to compounds offormula (53) can be achieved by reaction with an acid such astrifluoroacetic acid or hydrochloric acid, or by hydrogenolysisconditions such as palladium on carbon under hydrogen gas.

Similarly, compounds of formula (11) wherein R⁵ is -alkylN₂ can beconverted to compounds of formula (11) wherein R5 is-alkylNHSO₃NHCOOR_(c) by the conditions for the transformation ofcompounds of formula (42) to compounds of formula (51).

Compounds of formula (11) wherein R⁵ is -alkylNH₂ can be converted tocompounds of formula (11) wherein R5 is -alkylNHSO₂N(R_(a))COOR_(c) bythe conditions employed for the conversion of (51) to (52).

Compounds of formula (11) wherein R⁵ is -alkylNH₂ can be converted tocompounds of formula (11) wherein R⁵ is -alkylNHSO₂NR_(a)R_(b) by theconditions employed for the conversion of (52) to (53).

It should be understood that the above-described embodiments and thefollowing examples are given by way of illustration, not limitation.Various changes and modifications within the scope of the presentinvention will become apparent to those skilled in the art from thepresent description.

EXAMPLES Example 1 Preparation of1-Cyclobutylamino-4-hydroxy-1H-quinolin-2-one

Part A. Preparation of 2-(N′-benzylidene-hydrazino)-benzoic acid.

To a solution of 2-hydrazino-benzoic acid mono hydrochloric acid salt(13.66 g, 72.42 mmol) dissolved in water (580 mL) and ethanol (125 mL)was added a solution of benzaldehyde (7.35 mL, 72.42 mmol) in ethanol(20 mL) dropwise at room temperature. The reaction mixture was stirredat room temperature for an additional 3 hours. The resulting solid wascollected by filtration and dried in a vacuum oven to provide 12.0 g(69%) of 2-(N′-benzylidene-hydrazino)-benzoic acid as a yellow solid.

Part B. Preparation of 2-(N′-benzylidene-hydrazino)-benzoic acid methylester.

Method A:

To a round-bottomed flask containing a solution of the product from PartA (12.0 g, 49.95 mmol) dissolved in a solution of methanol (60 mL) andtetrahydrofuran (60 mL) was affixed with an addition funnel to the top.The round-bottomed flask was then placed in an ice bath, and vented to amineral oil bubbler. The addition funnel was then charged with asolution of

(trimethylsilyl)diazomethane (2.0 M in diethyl ether, 50 mL, 100 mmol),which was added dropwise over 20 minutes to the flask. Upon completeaddition the reaction mixture was capped and allowed to stir at roomtemperature for 16 hours. The resultant mixture was then concentratedunder vacuum and subjected to column chromatography on silica gel using2% ethyl acetate in hexanes as eluent to provide 11.0 g (87%) of2-(N′-benzylidene-hydrazino)-benzoic acid methyl ester.

Method B:

To a round-bottomed flask containing a solution of of the product fromPart A (12.0 g, 49.95 mmol) was added tetrahydrofuran (348 mL), followedby dimethylformamide dimethyl acetal (DMF-DMA, 13.2 mL, 99.9 mmol, 2eq). The solution was heated to reflux for 10 hours. At completion ofthe reaction, solvent was switched to toluene (100 mL), washed withhalf-saturated NaCl solution (3×20 mL), saturated NaCl solution (20 mL).Solvent was removed under reduced pressure and product was crystallizedfrom EtOAc/MeOH to provide 11.7 g (92%) of2-(N′-benzylidene-hydrazino)-benzoic acid methyl ester. MP 66.5-67.5° C.¹H NMR (400 MHz, DMSO-d₆) δppm 3.87 (s, 3 H), 6.83 (td, J=7.55, 1.10 Hz,1 H), 7.33-7.44 (m, 3 H), 7.50-7.54 (m, 1 H), 7.69-7.75 (m, 3 H), 7.85(dd, J= 8.03, 1.58 Hz, 1 H), 8.19 (s, 1 H), 11.00 (s, 1 H). ¹³C NMR(100MHz, DMSO-d₆)δ ppm 51.82 (CH₃), 108.71 (C), 112.96 (CH), 117.27 (CH),125.79 (2×CH), 128.14 (2×CH), 128.29(CH), 130.11 (CH), 134.14 (CH),134.49 (C), 140.64 (CH), 146.14 (C), 166.92 (C).

Part C. Preparation of2-[N′-benzylidene—N-(2-methoxycarbonyl-acetyl)-hydrazino]-benzoic acidmethyl ester.

To the product from Part B (21.62 g, 89.99 mmol) dissolved in toluene(150 mL) was added methyl 3-chloro-3-oxopropionate (9.65 mL, 89.99mmol). The mixture was then heated to reflux for 3hours, allowed to coolto room temperature, the toluene solvent removed under vacuum and theresultant oil left under vacuum for 16 hours The resulting solid formedwas collected and washed with ether to provide 24.68 g (77%) of2-[N′-benzylidene—N-(2-methoxycarbonyl-acetyl)-hydrazino]-benzoic acidmethyl ester.

Part D. Preparation of1-(benzylidene-amino)-2,4-dioxo-1,2,3,4-tetrahydro-qumoline-3-carboxyiicacid methyl ester.

The product from Part C (20 g, 56.43 mmol) was suspended in a solutionof sodium methoxide in methanol (0.5M, 112.9 mL, 56.43 mmol) and heatedto 50° C. for 3 hours. The mixture was allowed to cool to roomtemperature, then poured into a solution of water (300 mL), which wasthen acidified to pH=1 with a 2N aqueous hydrochloric acid solutionwhich caused a yellow solid to form. This solid was then collected byfiltration and dried in a vacuum oven to provide 17 g (94%) of1-(benzylidene-amino)-2,4-dioxo-1,2,3,4-tetrahydro-quinoline-3-carboxylicacid methyl ester as a yellow solid.

Part E. Preparation of 1-amino-4-hydroxy-1H-quinolin-2-one

The product from Part D (14.4 g, 44.68 mmol) and potassium hydroxide(34.53 g, 616.55 mmol) were dissolved in a mixture of dioxane (60 mL)and water (200 mL), A short-path distillation column was attached andthe solution heated to 115° C. in order to remove (distill off) thedioxane (60 mL) from the mixture The solution was then partially cooledand an additional 60 mL of dioxane added to the solution and distilledoff. This was done 2 more times (4×60 mL dioxane total) and theresulting aqueous solution was extracted with a mixture of 1/1:EtOAc/Et₂0 (200 mL) and the to the resultant aqueous solution was addeda solution of 12N HCl solution until the pH of the solution was 2, Thiscaused a solid to form, which was collected and dried in a vacuum ovento provide 6.8 g (86%) of 1-amino-4-hydroxy-1H-quinolin-2-one as ayellow solid.

Part F. Preparation of1-cyclobutylideneamino-4-hydroxy-1H-quinolin-2-one.

Method A:

To a suspension of the product from Part E (5.6 g, 31.79 mmol, 1 eq) andtrifluoroacetic acid (0.12 mL, 1.59 mmol) in benzene (55 mL) was addedcyclobutanone (5.94 mL, 79.47 mmol, 2.5 eq) and a dean-stark tubeattached. The mixture was then heated to reflux and over the next hourwater was collected in the dean-stark tube The solution was cooled toroom temperature, then an additional amount of cyclobutanone (2.38 mL,31.79 mmol, 1.0 eq) was added and the mixture again heated to reflux for30 min. After cooling again to room temperature, the mixture wasconcentrated under vacuum to provide 6.92 g (95%) of1-cyclobutylideneamino-4-hydroxy-1H-quinolin-2-one as a light greensolid.

Method B:

To a suspension of the product from Part E (10.6 g, 56.8 mmol, 94 wt %purity) and trichloroacetic acid (1.9 g, 11.4 mmol, 0.2 eq) in2-methyltetrahydrofuran (113 mL) was added cyclobutanone (8.5 mL, 113.5mmol, 2.0 eq). The reaction mixture was heated to reflux with aDean-Stark trap attached. The suspension was heated to reflux andstirred under reflux for 16 h. The suspension was cooled to 5° C. andstirred for 1 h., The suspension was then filtered. The product wasdried at 40QC under vacuum for 12 h to give 11.3 g (93 wt % purity=81%wt-adjusted yield) of 1-cyclobutylideneamino-4-hydroxy-1H-quinolin-2-oneas an off-white solid. ¹H NMR [(CD₃)₂SO] δ 1.94 (2 H, m), 2.68 (2 H, m),3.19 (2 H, m), 5.89 (1 H, s), 7.22 (1 H, m), 7.35 (1 H, dd), 7.56 (1 H,m), 7.87 (1 H, dd), 11.38 (1 H, br s); ¹³C NMR [(CD₃)₂SO] δ 12.9, 34.2,36.0, 97.8, 113.6, 114.7, 121,1, 122.5, 130.6, 137.4, 156.2, 159.8,182.3. MS-ESI: m/z 229 (M+H)⁺ and m/z 251 (M+Na)⁺.

Part G. Preparation of 1-cyclobutylamino-4-hydroxy-1H-quinolin-2-one

Method A:

To the product from Part F (0.25 g, 1.096 mmol) dissolved intrifluoroacetic acid (3 mL) was added triethylsilane (0.368 mL, 2.30mmol) and the mixture stirred at room temperature for 1 hour. To thismixture was added a solution of hexanes (10 mL), the mixture shaken andthe trifluoroacetic acid layer separated and concentrated under highvacuum to yield 0.21 g (83%) of 1-cyclobutylamino-4-hydroxy-1H-quinolin-2-one as an oil.

Method B:

To a three-necked flask with the product from Part F were chargedhydrazone (6.85 g, 30.0 mmol) and THF (102 ml), the resulting mixturewas cooled to 15° C. To the mixture was added BH₃Et₂NPh (4.2 g, 24.0mmol) dropwise keeing the reaction temperature below 25° C., Theresulting mixture was stirred at room temperature until less than 1% ofstarting material remains. Methanol (14 ml) was added slowly to quenchthe borane reagent. The resulting mixture was stirred at roomtemperature for 30 min. The organic solvents (MeOH and THF) were removedunder vacuum to about 35 ml. MeOH (70 ml) was added and the resultingmixture was concentrated to about 35 ml. More MeOH (28 ml) was added tothe mixture and the resulting mixture was heated to reflux (˜65° C.), 2NHCl (170 ml) solution was then added slowly keeping the temperatureabove 60° C., The resulting mixture was heated to 80° C. for 1 h, cooledslowly to room temperature, stirred at room temperature for 2 h, andfiltered. The mother liquor was circulated to rinse the flask. The wetcake was dried in a vacuum oven at 45° C. overnight to obtain 6.29product (90%) of 1-cyclobutylamino-4-hydroxy-1H-quinolin-2-one as awhite solid. ¹H NMR [(CD₃)₂SO] δ1.50 (1 H, m), 1.63 (1 H, m), 1.96 (4H,m), 3.62 (1 H, m),5.91 (1 H, s), 6.23 (1 H, d), 7.17 (1 H, m), 7.58 (1H, m), 7.82 (2 H, m), 11.40 (1 H, br s); ¹³C NMR [(CD₃)₂SO] δ14.5, 28.3,54.5, 96.9, 113.9, 114.7, 120.5, 122.3, 130.4, 139.4, 160.0, 160.9.

Example 2A Preparation of2-Amino-4-(methanesulfonylamino-methyl)-thiophene-3-sulfonic acid amide(Method A).

Part A. Preparation of 4-bromo-thiophene-3-carboxylic acid ethyl ester,

To a 0° C. solution of 3,4-dibromothiophene (1.0 Kg, 4.13 mol) intetrahydrofuran (7.4 Kg) was added iPrMgCl (2.0 M solution intetrahydrofuran, 2.58 Kg, 5.17 mol) keeping the temperature below 5° C.The resulting mixture was stirred at 0-5° C. for 5 hours. To the cooledGrignard solution was added ethyl chioroformate (896 g, 5.17 mol)dropwise keeping the temperature below 10° C. The resulting mixture waswarmed to room temperature, and stirred for 16 hours. Water (200 mL) wasadded to the reaction mixture, and the resulting mixture was stirred atroom temperature for 10 min The majority of the tetrahydrofuran was thenremoved under vacuum and ethyl acetate (4.5 Kg) was added to the mixturefollowed by IN aqueous hydrochloric acid. The layers were separated, andthe organic layer was washed with 12% brine (5.0 Kg) The solvent wasremoved under vacuum to give a yellow oil, which was filtered to removesalts to provide 956 g (98% yield) of 4-bromo-thiophene-3-carboxylicacid ethyl ester, which was used in the next step without furtherpurification. ¹H NMR (400 MHz, CDCl₃): δ 8.10 (d, 1 H, J=3.5 Hz), 7.30(d, 1 H, J=3.6 Hz), 4.34 (q, 2 H, J=7.10 Hz), 1.38 (t, 3 H, J=7.20 Hz);¹³C NMR (400 MHz, CDCl₃): δ14.49, 60.95, 110.49, 124.86, 130.93, 133.67,160.68.

Part B, Preparation of 4-bromo-5-nitro-thiophene-3-carboxylic acid ethylester.

To a flask containing sulfuric acid (1900 mL) at −10 to −15° C. wasadded the product from Part A (265 g, 1.13 mol) at a rate to maintainthe temperature at −10° C. To this mixture was added a mixture of fumingnitric acid (75 g, 1.19 mol) and sulfuric acid (350 mL) whilemaintaining the temperature at −10° C. The reaction mixture was thencarefully poured, in portions, into a mixture of water (1 L) and ice (12Kg), and the product immediately precipitated during the addition. Theproduct was isolated by filtration and the wet cake was washed withwater (5 L), 10% NaHCC>3 (5 L), followed by water (5 L), and petroleumether (4 L), and dried in a vacuum oven to provide 302 g of the crudetitle product. This crude material was then recrystallized fromethanol/t-butyl methyl ether to provide 235 g (74%) of4-bromo-5-nitro-thiophene-3-carboxylic acid ethyl ester. ¹H—NMR(DMSO-d₆): 8.68 (s, 1 H), 4.32 (q, 2 H, J=7.09), 1.34 (t, 3 H, J=7.07);¹³C—NMR (DMSO-d₆); 159.11, 147.13, 138.77, 131.17, 112.57, 61.25, 14.06.Melting point: 94-95° C.

Part C. Preparation of 4-benzylsulfanyl-5-nitro-thiophene-3-carboxylicacid ethyl ester.

The product from Part B (400 g, 1.43 mol) and ethanol (5.6 L) werecharged to a 12 L 3-neck round-bottomed flask and the yellow slurry wascooled to 12-14° C. Potassium carbonate (211.2 g, 1.53 mol) was added asa solution in water (800 mL) all at once. The temperature increased to16° C., most of the solids dissolved and the solution became pink/red incolor. Benzyl mercaptan (189.8 g, 1.53 mol) was added via additionfunnel over 1.75 h. The temperature was maintained at 16-20° C. duringthe addition. After a rinse with ethanol (50 mL), the slurry (productprecipitated during addition) was mixed at ambient temperature for anadditional 2.5 h. Water (5 L) was added over 40 min, and the slurry wasstirred at ambient temperature for 1.5 h. The product was isolated byfiltration, rinsed with ethanol/water (1/1, 2×1 L) followed by coldheptane (2×1 L). The product was dried at 40° C. under vacuum to provide4-benzylsulfanyl-5-nitro-thiophene-3-carboxylic acid ethyl ester (430.8g, 93%).

Part D. Preparation of(4-benzylsulfanyl-5-nitro-thiophen-3-yl)-methanol.

To a flask equipped with an addition funnel was added the product fromPart C (5.0 g, 15.46 mmol) and dichloromethane (50 mL). The mixture wasthen cooled and maintained at-43° C. (dry ice/acetonitrile) whendiisobutylaluminum hydride (DIBAL-H, 1M in CH₂Cl₂, 32.5 ml, 32.5 mmol)was slowly added over 45 minutes. After the addition was complete, themixture was allowed to stir at −43° C. for 2 hours. The dryice/acetonitrile bath was replaced with an ice bath and then the mixturewas slowly quenched with 1M aqueous HCl (100 mL). The layers wereseparated and the organic layer was filtered through celite,concentrated under vacuum and subjected to purification by silica gelcolumn chromatography (5% to 50% ethyl acetate/hexanes) to provide 3.28g (75%) of (4-benzylsulfanyl-5-nitro-thiophen-3-yl)-methanol as ayellow-orange colored oil that solidifies upon standing. ¹H NMR (300MHz, DMSO-d₆)δ ppm 4.26 (s, 2 H) 4.33 (dd, J=5.52, 1.10 Hz, 2 H) 7.14-7.29 (m, 5 H) 7.78 (s, 1 H).

Part E. Preparation of3-benzylsulfanyl-4-chloromethyl-2-nitro-thiophene.

A solution of the product from Part D (35.59 g, 126.5 mmol) in toluene(175 mL) was cooled to 6° C. and DMF (0.925 g, 12.65 mmol) was added.Then a solution of thionyl chloride (16.25 g, 136.59 mmol) in toluene(17 mL) was added over 18 min. The solution was then warmed to roomtemperature and mixed for 1.5 h at room temperature. The reaction wasquenched by addition of 10% sodium carbonate (71 mL). The majority ofthe aqueous phase was removed and the remaining solution was filteredthrough celite. The rest of the aqueous phase was removed then theorganic solution concentrated to provide 32.46 g (85.6%) of3-benzylsulfanyl-4-chloromethyl-2-nitro-thiophene as an oil.

Part F. Preparation of N-tert-bntylester—N-(4-benzylsulfanyl-5-nitro-thiophen-3-yImethyi)-methanesulfonamide.

Method A:

The product from Part E (32.46 g, 108.27 mmol) was dissolved in dimethylacetamide (162 mL) and to the solution was added N-tert-butyl ester-methanesulfonamide (22.3 g, 114.22 mmol) and potassium carbonate (10.51g, 76.04 mmol). The resulting solution was heated to 55 ° C. for 16 h.To the cooled reaction mixture was added ethyl acetate (444 mL) and thesolution was washed with a 7% aqueous sodium chloride (3×444 mL)solution. The solvent was removed under vacuum and the residue wasdissolved in ethanol. The product crystallized and was isolated byfiltration and washed with cold ethanol to provide 39 g (80%) ofN-tert-butylester—N-(4-benzylsuifanyl-5-nitro-thiophen-3-ylmethyl-methanesulfonamideas a light yellow solid. ¹H—NMR(DMSO-d₆) δ1.42 (9H, s), 3.41 (3 H, s),4.19 (2 H, s), 4.63 (2 H, s), 7.1-7.3 (5H, m), 7.62 (1 H, s); ¹³C—NMR(DMSO-d₆) δ 27.50, 39.24, 41.76, 44.99, 84.09, 126.92, 127.40, 127.93,128.26, 131.33, 136.21, 141.48, 150.16, 150.81; DCI-MS 476 (M+18).

Method B:

To a solution of N-Boc methanesulfonamide (12.00 g, 61.5 mmole) and 1Mof trimethylphosphine (61.5 mL, 61.5 mmole) in THF was added(4-benzylsulfanyl-5-nitro-thiophen-3-yl)-methanol (11.5 g, 40.9 mmole)in 135 mL THF over 15 min at ˜25° C. The resulting solution was stirredat ˜25° C. for ˜10 min., and 26.7 g of 40% DEAD solution in toluene(26.7 g, 61.4 mmole) added slowly over ˜10 min (slightly exothermic,water bath cooling). The reaction mixture was stirred at ˜25° C.overnight or until the starting material was consumed as indicated byHPLC. The reaction mixture was concentrated to dryness, and ethylacetate (200 mL) and 5% NaHCO₃ aq. Solution (200 mL) added. The upperorganic was washed with 5% NaHCO₃ (200 mL×2), and 25% brine (200 mL).The organic was dried over MgSO₄, filtered. The filtrate wasconcentrated to ˜50-60 mL volume (some solid), diluted with heptane (50mL). The solid was filtered off, rinsed with ethyl acetate: heptane(1:1, 20 mL). The filtrate was concentrated to ˜40 mL volume,chromatographed om a silica gel column (250 g), eluting with heptane:acetone (4:1), The main fractions of product were pooled, andconcentrated to dryness to yield an oil (18.0 g), which was crystallizedfrom abs ethanol to give 14.1 g product of N-tert-butyl ester-N-(4-benzylsulfanyl-5-nitro-thiophen-3-ylmethyl)-methanesulfonamide as alight yellow solid.

Part G. Preparation of 4-[(N-tert-butylester-methanesulfonyl-amino)-methyl]-2-nitro-thiophene-3-sulfonylchloride.

Method A:

The product from Part F (18.0 g, 39.3 mmole) was dissolved in a mixtureof dichloromethane: acetic acid: water (225 mL: 75 mL: 75 mL). Theresulting mixture was cooled down to −5° C. Chlorine gas (minimum 3 eq.)was bubbled slowly through the mixture for a few minutes at the internaltemperature of <5° C. and the mixture stirred at 0° C. for 1 h. thelower organic phase was then separated and washed with 25% brine (200mL). The organic phase was dried over sodium sulfate, filtered, andconcentrated to approx. 30 mL volume. Heptane (100 mL) was added slowly.The resulting slurry was stirred at room temperature for Ih, filtered,rinsed with heptane (30 mL), and dried under vacuum to provide 14.0 g,(82%) of 4-[(N-tert-butylester-methanesulfonyl-amino)-methyl]-2-nitro-thiophene-3-sulfonylchloride as a solid, ¹H—NMR(CDCl₃) δ 1.51 (9H, s), 3.40 (3 H, s), 5.07(2 H, s), 7.55 (1 H, s); ¹³C—NMR(CDCl₃) δ 28.15, 42.40, 46.88, 86.11,123.95, 134.28, 138.64, 150.34; DCI-MS 452 (M+18).

Method B:

The product from Part F (18.4 g, 40.1 mmole) was dissolved in a mixtureCH₂Cl₂: HOAc: HO₂(140 mL: 20 mL: 40 mL). The resulting mixture wascooled down to 10° C. 1,3-Dichloro-5,5-dimethylhydantoin (24.0 g, 121mmole) in 80 mL of CH₂Cl₂ was added portionwise at ˜10° C. and themixture stirred at 10° C. for 20 h. 100 mL of 5% sodium metabisulfitesolution was added slowly at <25° C., followed by addition oflOO mL of20% potassium phosphate dibasic solution. The lower organic phase wasseparated and used directly in the next step without furtherpurification. However, an analytical sample of4-(N-t-butoxycarbonylmethanesulfonylamino-methyl)-2-nitro-thiophene-3-sulfonylchlorid was prepared by crytaliization from heptane; Mp ˜75° C.(decomposed, uncorrected); ¹H—NMR (CDCl₃) δ 1.51 (9H, s), 3.40 (3 H, s),5.07 (2 H, s), 7.55 (1 H, s); ¹³C—NMR(CDCl₃) 5.28.15, 42.40, 46.88,86.11, 123.95, 134.28, 138.64, 150.34; DCI-MS 452 (M+18),

Part H Preparation of 4-[(N-tert-butylester-methanesulfonyl-amino)-methyl]-2-nitro-thiophene-3-sulfonic acidamide.

To a 500 mL flask were charged the product from Part G (13.95 g, 32.0mmole), and acetonitrile (200 mL). The solution was cooled down to −5°C., and 7.0 mL of concentrated ammonium hydroxide aqueous solution wasadded dropwise at <5° C. The orange colored slurry was mixed at 0 ° C.for Ih, then concentrated to 50 mL volume. The mixture was diluted withethyl acetate (200 mL), 5% sodium bicarbonate (100 mL) and 25% brine(100 mL), The upper organic phase was washed with 25% brine (150 mL),dried over magnesium sulfate, and filtered. The filtrate wasconcentrated to dryness. The crude product was chromatographed on silicagel (300 g), eluting with heptane: acetone (3:1) to (2:1) to provide 9.7g (73%) of 4-[(N-tert-butylester-methanesulfonyl-amino)-methyl]-2-nitro-thiophene-3-sulfonic acidamide as a solid. ¹H—NMR(DMSO-d₆) δ 1.44 (9H, s), 3.49 (3 H, s), 4.93 (2H, s), 7.57 (1 H, s), 7.93 (2 H, s); ¹³C—NMR(DMSO-d₆) δ 27.51, 41.79,46.58, 84.19, 125.48, 137.28, 137.32, 150.06; DCI-MS 433 (M+18).

Part I. Preparation of4-(methanesulfonylamino-methyl)-2-nitro-thiophene-3-sulfonic acid amide.

To the product from Part H (9.7 g, 23.3 mmol) in acetonitrile (200 mL)was added 22.0 mL of concentrated hydrochloric acid solution at roomtemperature. The reaction mixture was stirred at room temperature for 8hr. The light-yellow solution was concentrated to 40 mL volume.Isopropyl acetate (150 mL), and 25% brine (100 mL) were added The upperorganic phase was separated, and the lower aqueous phase extracted with2-propanol (75 mL×2). The combined organic extracts were washedcarefully with a mixture of 5% sodium bicarbonate (100 mL), and 25%brine (100 mL). The organic solution was dried over magnesium sulfate,filtered, and concentrated to 40-50 mL volume. The slurry was stirred atroom temperature for 5 hr, and 0° C. for 2h. The solid was collected byfiltration, then dried at 35° C. under vacuum overnight to provide 5.9 g(80%) of 4-(methanesulfonylamino-methyl) -2-nitro-thiophene-3-sulfonicacid amide. H—NMR(DMSO-d₆) δ 2.96 (3H, s), 4.35 (2 H, s), 7.62 (2 H, s,br), 7.86 (1H, s), 7.88 (2H, s, br); ¹³C—NMR(DMSO-d₆) □39.94, 42.01,127.22, 137.33, 137.79, 149.63; DCI-MS 333 (M+18).

Part J. Preparation of2-amino-4-(methanesuIfonylamino-methyl)-thiophene-3-sulfonic acid amide.

The product from Part I (5.90 g, 18.73 mmol) was hydrogenated with 5.90g of 10% Pd/C in tetrahydrofuran (170 mL) at 25-30° C. overnight. Thereaction mixture was filtered, and rinsed with tetrahydrofuran (50 mL).The filtrate was concentrated to 30 mL volume, The resulting suspensionwas stirred at 25° C. for 2 h, and diluted with hexane (30 mL). Theoff-white solid that formed was filtered, rinsed with hexane (20 mL),and dried at 25° C. under vacuum to provide 5.00 g (93%) of2-amino-4-(methanesulfonylamino-methyl)-thiophene-3-sulfonic acid amide.¹H—NMR(DMSO-d₆) δ 2.90 (3H, s), 4.16 (2H, d, J=6.4 Hz), 6.25 (1H, s),6.62 (2H, s), 7.14 (2H, s), 7.27 (1H, t, J=6.4 Hz); ¹³C—NMR (DMSO-d₆) δ39.80, 41.77, 103.10, 110.81, 133.96, 157.66; ESI-MS 308 (M+23), 286(M+l); Anal. Calcd for C₆H₁₁N₃O₄S₃: C, 25.25; H, 3.89; N, 14.73; S,33.71. Found: C, 25.37; H, 3.74; N, 14.42; S, 33.36.

Example 2B Preparation of2-Amino-4-(methanesulfonylamino-methyl)-thiophene-3-sulfonic acid amide(Method B).

Part A. Preparation of 4-Bromothiophene-3-carbonitrile.

To a three-necked flask was charged THF (8.3 L) and dibromothiophene(435.5 g, 1.8 mol), the solution was cooled to 0° C., to the solutionwas added iPrMgCl (2.0 M solution in THF, 1125 ml, 2.25 mol) slowlykeeping the temperature below 5° C., The resulting mixture was stirredat 0˜5° C. until HPLC indicate that the s m, was less than 1%. To thecooled reaction mixture was added a solution of TsCN (416 g, 2.25 mol)in THF (850 ml) dropwise keeping temperature below 5° C. The resultingmixture was stirred at 0° C. until the intermediate Grignard wasconsumed. To the reaction mixture was added H2O (100 ml) and theresulting mixture was stirred for 10 min The THF was partially removedunder vacumm (to about 800 ml). EtOAc (5.0 L) was added to the mixturefollowed by 1N HCl (4.0 L), the resulting mixture was stirred for 10min. The organic layer was separated, washed with 5% NaHCO3 (4.0 L)followed by 12% brine (4.0 L). The organic layer was then treated withcarbon (40 g) and dried over Na2SO4 and filtered through a filter agent,The filtrate was concentrated to obtain the product, which was furtherdried under high vacuum to give 332 g of product as beige solid (94.3%weight adjusted yield, HPLC purity of 96.5% pa). A small sample of theproduct was further purified by crystallization with EtOAc/Heptane toobtain analytical standard. ¹H NMR (400 MHz, CDCl₃): δ 7.94 (d, 1 H,J=3.3 Hz), 7.35 (d, 1 H, J=3.3 Hz); ¹³C NMR (400 MHz, CDCl₃): δ 112.23,113.51, 114.58, 124.89, 136.35.

Part B. Preparation of 4-Bromo-5-nitrothiophene-3-carbonitrile.

To a 3 L of jacketed RB-flask equipped with a mechanical stirrer wasadded cone, H₂SO₄ (1500 mL). The content was cooled with a circulationbath to −20° and to the flask was added the product from Part A (149 g,792.34 mmol) slowly (the process is not very exothermic) maintaininginternal temperature below −10° C. To the above reaction mixture wasthen added a mixture of fuming nitric acid (45 mL, reagent grade,fuming, >90) and sulfuric acid (200 mL) slowly (exothermic) keeping theinternal temperature slightly below −10° C. After the addition wascompleted, the circulation bath was disconnected and the reactionmixture was siowly warmed to ambient temperature within 3 hours. Thereaction completion was monitored by HPLC. Upon completion of thereaction, the reaction mixture was poured into a mixture of water (1 L)and ice (14 Kg) in portions with vigorous mechanical stirring. The solidproduct precipitated out and ice (14 Kg) was added in portions,alternating with the addition of the reaction mixture. The solid productwas filtered, washed with water (2×1 L), half saturated aqueous NaHCO₃solution (2 L), followed by another water wash (2 L), and a petroleumether wash (1 L), dried on filter under nitrogen flow, and further driedin vacuum oven at 45° C. overnight to give 184,7 g of crude4-bromo-5-nitrothiophene-3-carbonitriie (98% weight adjusted yield,purity 97.3% pa). The crude product (184.7 g) was mixed with a mixtureof MTBE-heptane-ab.EtOH (1010:1, 1847 mL). The suspension was heated toreflux (61° C.), held at reflux for 30 min, then slowly cooled toambient temperature The product was collected by filtration, washed oncewith heptane (2 L), dried under nitrogen for 3 hours, and then furtherdried in vacuum oven at 45 ° C. for 4 hours to give 175 g of purified4-bromo-5-nitrothiophene-3-carbonitrile (95% yield). MP: 176-178° C.¹H—NMR (DMSO-d₆): 8.99 (s, 1 H). ¹³C—NMR (DMSO-d₆): 142.66 (CH), 142.66,114.72, 113.89, 112.40. Elemental analysis: Calcd for C₅H₁BrN₂O₂S: C,25.77%; H, 0.43%; N, 12.02%; Br, 34.29%; S, 13.76%. Found: C, 25,70%; H,0.15%; N, 11.84%; Br, 34.01%; S, 13.86%.

Part C. Preparation of 4-(Benzylthio)-5-nitrothiophene-3-carbonitrile.

To a suspension of the product from Part B (16.7 g, 71.7 mmol) in THF(83 mL) was added a solution of K₂CO₃ (10.9 g, 78.8 mmol) in H₂O (67mL). The resulting slurry was cooled to 10-15° C. and a solution ofbenzyl mercaptan (9.8 g, 78.8 mmol) in THF (51 mL) was added over 40minutes via addition funnel. After stirring at RT for 1.5 h, thereaction mixture was diluted with EtOAc (160 mL) and a pH 7 buffer (160mL). The layers were separated and the organic phase was dried overNa₂SO₄ and concentrated in vacuo. The crude material was taken up inEtOH (150 mL), The solution was mixed at RT and the product graduallycrystallized. After mixing for 4 h, H₂O (150 mL) was added over 20minutes and the slurry was stirred an additional 1.5 h. The product wasisolated by filtration to give of4-(benzylthio)-5-nitrothiophene-3-carbonitrile as a yellow solid (19.55g, 98%). ¹H NMR (DMSO-D6): 8.87 (s, 1 H), 7.28 (m, 5H), 4.54 (s, 2 H).

Part D. Preparation of 4—Cyano-2-nitro-thiophene-3-sulfonic acid amide,

Chlorine gas (106.1 g, 1.50 mol) was slowly bubbled into a suspension ofthe product from Part C (100.0 g, 363.9 mmol) in HOAc (800 mL) and H₂O(200 mL) over 70 minutes at 0-8° C. The reaction mixture was purged withnitrogen then H₂O (350 mL) was added over 20 minutes and the slurry wascooled to 0-5° C. The product was isolated by filtration and dried at RTto give 79.39 g of the sulfonyl chloride, which was used directly in thenext step without isolation. A solution of thiophenesulfonyl chloride(134.80 g, 0.5335 mol) in THF (1150 mL) was added to a solution of THF(3350 mL) containing ammonia (22.56 g, 1.325 mol) at ca. −50° C. over1.5 hr. to give 4-cyano -2-nitro-thiophene-3-sulfonic acid amide. Theexcess ammonia and solvent were removed under reduced pressure startingto give a thick slurry. Residual THF was chased with MeOH (500 mL) underreduced pressure, and the residue treated with MeOH (700 mL) to give adark slurry The slurry was mixed at 0 to 10° C. for 35 min. and thesolid collected by filtration (the crude product was analyzed by HPCL togive a 81% yield). The crude product solid was further purified byrinsing with ice-cold MeOH-water (1:1 v/v, 2×100 mL) followed by water(1×200 and 1×250 mL). The solid was dried on the filter to afford 79.80gof 4—Cyano-2-nitro-thiophene-3-sulfonic acid amide (64.1% yield, with14.25 g of the product lost to the filtrate). ¹H NMR (DMSO-d6): δ=8.90(s, 1H), 8.22 (br s, 2H). ¹³C NMR (DMSO-d6): δ=149.5, 142.1, 140.7,112.3, 109.7.

Part E. Preparation of 2-Amino-4-cyanothiophene-3-sulfonamide.

A solution of the product from Part D (77 g, 330.1 mmol) in THF (1500mL) was treated with 10% Pd on carbon (77 g) at 40 psi hydrogen pressureat room temperature for 32 hr. The mixture was filtered and the solventremoved under reduced pressure to give a solid (66.60 g). The solid wasplaced under oil pump vacuum at room temperature to afford2-amino-4-cyanothiophene-3-sulfonamide (65.85 g, 98.1% yield). The solid(59.97 g) was further purified by treating with refluxing absolute EtOH(1000 mL) for 3.75 hr, then cooling and filtering at 1.4° C. and dryingon the funnel at room temperature to a constant wt. to give a total of53.39 g of purified 2-amino-4-cyanothiophene-3-sulfonamide in threecrops (79.6% yield). ¹H NMR (DMSO-d6): δ=7.48 (s, 1H), 7.33 (br s, 2H),6.92 (br s, 2H). ¹³C NMR (DMSO-d6): δ=159.6, 121.2, 113.8, 111.4, 106.3.

Part F. Preparation of 2-Amino-4-(aminomethyl)thiophene-3-sulfonamide,

To a solution of the product from Part E (10.00 g, 49.20 mmol) in THF(100 mL) was added borane-methyl sulfide complex (BMS, 2.0 M in THF,70.21 g, 164.24 mmol) over 3 minutes at ambient temperature. Thereaction was stirred for 30 minutes and the reaction completion wasmonitored by HPLC, Upon completion of the reaction, the solvent wasdistilled until a thick slurry was obtained. The mixture was cooled to15° C. and MeOH (75 mL) was added dropwise while maintaining thetemperature at <40° C. The resulting solution was concentrated and theresidue was chase with MeOH (2×100 mL) at atmospheric pressure to avolume of ca, 50 mL, The reaction was cooled to 14° C. and MeOH-HCl (2M,74 mL) was added over 6 minutes to give an orange slurry. To this slurrywas added MeOH (150mL) and the mixture was concentrated in vacuo to anoil. The oil was chased with MeOH (2×100 mL) to give 13.41 g of crudeproduct as an oil that solidified on cooling. A portion of thisdihydrochloride was purified via column chromatography to affordanalytical sample of 2-amino-4-(aminomethyl)thiopheiie-3-sulfonamide,(¹H NMR (DMSO-D6): 6.54 (s, 2 H), 6.22 (s, 1 H), 4.59 (vbr s, 3 H), 3.66(s, 2 H),

Part G. Preparation of2-Amino-4-(methylsulfonamidomethyl)thiophene-3-sulfonamide.

Methanesulfonyl chloride (323.4 mg, 2.823 mmol) was added to a solutionof the product from Part F (500.3 mg, 2.414 mmol) in THF (5.0 mL), NMP(1.0 mL), and triethylamine (TEA, 0.841 mL, 6.03 mmol) over 23 minutesat ambient temperature. The reaction mixture was stirred at ambienttemperature for 1.0 hour. THF (10 mL) was added to the slurry, and themixture was stirred for 1.0 hour then filtered. The filter cake waswashed with THF (10 mL) and the combined liquors concentrated in vacuoto give an oil. Residual THF was chased with dichloromethane (2×10 mL)in vacuo to afford 1.546 g of a clear oil. A portion of this oil (1.273g) was dissolved in EtOAc (12.7 mL) and washed with 7% NaCl solution(4×4.2 mL) The organic phase was concentrated until solid NaCl began toform. EtOAc (10 mL) was added and the mixture was filtered. The filtratewas concentrated in vacuo to ca. 2.5 mL volume at which time2-amino-4-(methylsulfonamidomethyl) thiophene-3-sulfonamide begancrystallizing out as platelets. The combined aqueous was extracted withEtOAc (2×5 mL). The resulting organic phase was added to the EtOAc fromabove, Dichloromethane (2.5 mL) was added to the combined organic phasefollowed by the addition of heptane (2.5 mL) over 27 minutes. Theresulting slurry was mixed at −12 to 0° C. for 50 minutes then filtered.The filter cake was dried on the funnel with a nitrogen flow to give356.2 mg of light-beige solid (¹H NMR (DMSO-D6): 7.27 (t, 1 H), 7.14 (s,2 H), 6.62 (s, 2 H), 6.25 (s, 1 H), 4.17 (d, 2 H), 2.90 (s, 3 H).

Example 3 Preparation of N-[(3-{1-[(cyclobutyl)amino]-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-yl}-1,1-dioxo-1,4-dihydro-1λ⁶-thieno[2,3-e][1,2,4]thiadiazin-7-yl)methyl]methanesulfonamide (Compound I)

Part A. Preparation of (Bis-methylsulfanyl-methylene)-methyl-sulfoniumtetrafluoroborate.

Dimethyl sulfate (22.84 mL, 240 mmol) and dimethyl trithiocarbonate(26.48 mL, 240 mmol) were added to acetonitrile (80 mL). The resultantdark yellow solution was heated to 90° C. for 2 hours. The mixture wasthen allowed to cool to 55° C. and then a solution of tetrafluoroboricacid (54% in diethyl ether, 48 mL) was added over 5 min time. Theresultant solution was stirred for an additional 15 min, followed bypouring it into a solution of ice-cold diethyl ether (600 mL), The whitesolid that formed was collected and washed with diethyl ether (3×50 mL)and dried in a vacuum oven to provide (bis-methylsulfanyl-methylene)-methyl-sulfonium tetrafluoroborate salt (47.3 g, 83%) as acolorless solid.

Part B. Preparation ofN-[3-{1-[(cyclobutyl)amino]-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-yl}-1,1-dioxo-1,4-dihydro-1λ⁶-thieno[2,3-e][1,2,4]thiadiazin-7-yl)methyl]methane-sulfonamide.

The product from Example 1 (18.0 g, 78.3 mmol) was dissolved in dioxane(157 mL) and then diethyl isopropylamine (80.5 g, 626.4 mmol) added,then the solution cooled to 0° C. followed by the addition of(bis-methylsulfanyl-methylene)-methyl-sulfonium tetrafluoroborate sait(52,4 g, 218.3 mmol) in portions. The resultant solution was stirred atroom temperature for 2 hours, followed by the addition of ethyl acetate(500 mL) and water (500 mL). The mixture was extracted and the resultantorganic layer separated then dried over magnesium sulfate. The organicsolution was then concentrated under vacuum to provide an orange oilwhich was dissolved in acetonitrile (150 mL) and added dropwise over 20min to a solution of the product from Example 2A or Example 2B (18.18 g,63.8 mmol) in acetonitrile (100mL) heated to 85° C. The resultantsolution was heated at 85° C. for an additional 2.5 hours, then allowedto cool to room temperature and sit overnight without stirring. After 24hours a solid had formed, which was collected and washed withacetonotrile (2×50 mL), then dried under vacuum to provide 27.0 g (80%)ofN-[(3-{l-[(cyclobutyl)amino]-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-yl}-1,1-dioxo-1,4-dihydro-1λ⁶-thieno[2,3-e][1,2,4]thiadiazin-7-yl)methyl]methanesulfonamide (i.e., Compound I) as a solid, ¹H—NMR(300 MHz,DMSO-d₆) δ 14.46 (bs, 1 H), 8.15 (m, 1 H), 8.05 (d, J=8.4 Hz, 1 H), 7.86(m, 1 H), 7.75 (t, J=6.3 Hz, 1 H), 7.42 (m, 2 H), 6.45 (bs, 1 H), 4.30(d, J=5.1 Hz, 2 H), 3.76 (m, 1 H),2.99 (s, 3 H), 2.03 (m, 4 H), 1.57 (m,2 H); ESI-MS 524 (M+H)⁺.

Example 4 Preparation ofN-[(3-{1-[(Cyclopropylmethyl)amino]-4-hydroxy-2-oxo-1,2-diliydroquinolin-3-yl}-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-7-yl)methyl]methane-sulfonamide(Compound II).

Ccompound II was prepared according to the procedure described inExample 353 of U.S. patent application Ser. No. 10/699,513, the entirecontent of which is incorporated herein by reference. The procedure isprovided below:

2-(N′-Benzylidene-hydrazino)-benzoic acid (5.0 g, 20.81 mmol) in 1:1tetrahydrofuran and methanol (50 mL) was reacted with a solution oftrimethylsilyl diazomethane in hexanes (2.0M, 12 mL, 25.0 mmol) at 0° C.for 1 hour then stirred at 25° C. for 48 hours. The solvent was removedunder vacuum to give methyl 2-[2-benzylidenehydrazino]benzoate as asolid (6.00 g, 100%). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 3.87 (s, 3 H) 6.84(td, J=7.54, 1.10 Hz, 1 H) 7.41 (m, 3 H) 7.54 (m, 1 H) 7.74 (m, 3 H)7.86 (dd, J=8.09, 1.47 Hz, 1 H) 8.21 (s, 1 H) 11.02 (s, 1 H),

Methyl 2-[2-benzylidenehydrazino]benzoate (5.29 g, 20.81 mmol) intoluene (80 mL) was reacted with ethyl chlotomalonate (2.68 mL, 25.0mmol) at reflux for 4 hours. The reaction mixture was cooled to 25° C.and concentrated under vacuum The residue was triturated with diethylether and hexanes (3:1) to give methyl2-[2-benzylidene-1-(3-ethoxy-3-oxopropanoyl)hydrazino]benzoate (5.17 g,70%), MS (DCI) m/z 355 (M+H)⁺. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 3.32 (s,2 H) 3.69 (s, 3 H) 3.73 (s, 3 H) 7.16 (s, 1 H) 7.32 (dd, J=7.72, 1.30Hz, 1 H) 7.40 (m, 3 H) 7.63 (m, 2 H) 7.70 (td, J=7.63, 1.29 Hz, 1 H)7.85 (td, J=7.72, 1.47 Hz, 1 H) 8.10 (dd, J=7.72, 1.47 Hz, 1 H).

Methyl 2-[2-benzylidene-1-(3-ethoxy-3-oxopropanoyl)hydrazino]benzoate(5.17 g, 14.59 mmol) in ethanol (100 mL) was reacted with sodiumethoxide (21% by weight in ethanol, 5.50 mL, 14.60 mmol) at 25° C. thenheated at 50° C. for 1 hour. After cooling to 25° C., the reactionmixture was poured into water, acidified to pH 4 with 1M hydrochloricacid and extracted with ethyl acetate. The organic layer was dried overanhydrous sodium sulfate, filtered and the solvent removed under vacuumto give ethyl4-hydroxy-2-oxo-1-{[phenylmethylene]amino}-1,2-dihydroquinoline-3-carboxylate(4.51 g, 96%). MS (DCI) m/z 323 (M+H)⁺. ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.73 (s, 3 H) 7.21 (m, 1 H) 7.56 (m, 5H) 7.95 (m, 2 H) 8.03 (d, J=7.72Hz, 1 H) 9.08 (s, 1 H).

To a solution of 25% by weight aqueous potassium hydroxide (200 mL) and1,4-dioxane (50 mL) heated to 90-100° C. was added portion wise ethyl4-hydroxy-2-oxo-1-{[phenylmethylene]amino}-1,2-dihydroquinoline-3-carboxylate(6.72 g, 20.0 mmol). The reaction mixture was heated at reflux for 90minutes allowing distillation to occur and additional water and dioxane(30 mL each) were added to the reaction vessel to reach the originalvolume. The mixture was refluxed for an additional 90 minutes withdistillation, cooled, washed with 200 mL of 1:1 diethyl ether/ethylacetate, acidified with concentrated hydrochloric acid to pH 2 and theresulting solid was collected by filtration, washed with water and driedto constant mass to give 1-amino-4-hydroxyquinolin-2(1 H)-one as a tansold (3.22 g, 91% yield), MS (DCI) m/z 177 (M+H)+. ¹H NMR (300 MHz,DMSO-d₆) δ 5.56 (s, 2 H) 5.94 (s, 1 H) 7.20 (t, J=7.54 Hz, 1 H) 7.62 (m,1 H) 7.85 (m, 2 H) 11.33 (s, 1 H).

To the suspension of 1-amino-4-hydroxyquinolin-2(1 H)-one (1.033 g, 5.86mmol) in methanol (58 mL) was added acetic acid (0.29 mL) andcyclopropylcarboxaldehyde (482 □L, 6.45 mmol) followed by the additionof sodium cyanoborohydride (744.6 mg, 11.85 mmol) at room temperature.The suspension was stirred at room temperature overnight and quenchedwith half saturated brine (100 mL) and sodium bicarbonate (425 mg, 5.06mmol). The mixture was extracted with ethyl acetate (300 mL) and theorganic layer was separated and washed with half saturated brine (2×50mL) The combined aqueous layers were extracted with dichloromethane(2×100 mL). The combined organic solution was dried with magnesiumsulfate, filtered and concentrated, to give(1-[(cyclopropylmethyl)amino]-4-hydroxyquinolin -2(1 H)-one) which wasused without any purification. ¹H NMR (300 MHz, DMSO-d₆) δ 0.09 (m, 2 H)0.40 (m, 2 H) 0.95 (m, 1 H) 2.70 (t, J=6.43 Hz, 2 H) 5.91 (s, 1 H) 6.10(t, J=6.07 Hz, 1 H) 7.23 (m, 1 H) 7.62 (t, J=7.17 Hz, 1 H) 7.87 (m, 2 H)11.42 (br s, 1 H).

To the suspension of 1-[(cyclopropylmethyl)amino]-4-hydroxyquinolin-2(1H)-one (984.4 mg, 4.28 mmol) in 1,4-dioxane (40 mL) was added pyridine(2.8 mL, 34.6 mmol) and tris(methylthio)methyl methyl sulfate (preparedusing the procedures in SYNTHESIS, 22-25, 1988; M. Barbero, S. Cadamuro,I. Degani, R, Fochi, A. Gatti, V, Regondi) (2.26 g, 8.55 mmol) at roomtemperature. The suspension was put in a preheated oil bath at 55° C.and stirred for 15 minutes. To the

solution was added another portion of tris(methyithio)methyl methylsulfate (2.26 g, 8.55 mmol) and the mixture was stirred at 55° C. for 15minutes and cooled to room temperature. The mixture was concentrated invacuo and the residue was diluted with dichloromethane and loaded on asilica gel column and eluted with dichloromethane, 2% ethylacetate/dichloromethane and then 5% ethyl acetate/dichloromethane togive 3-[bis(methylthio)methylene]-1-[(cyclopropylmethyl)amino] quinoline-2,4(1 H, 3 H)-dione (852.1 mg, 60%). ¹HNMR(300 MHz, DMSO-d₆) δ 0.15 (m,2 H) 0.42 (m, 2 H) 0 98 (m, 1 H)2.61 (s, 6H)2.73 (t, J=6.43 Hz, 2 H)6.05 (t, J=5.88 Hz, 1 H) 7.15 (m, 1 H) 7.64 (m, 1 H) 7.76 (d, J=8.09 Hz,1 H) 7.98 (m, 1 H).

Methyl 4-(benzylthio)-5-nitrothiophene-3-carboxylate was preparedaccording to the procedure as described in Stanetty, P. et. al., JOURNALOF HETEROCYCLIC CHEMISTRY, 36, 761-765 (1999).

Methyl 4-(benzylthio)-5-nitrothiophene-3-carboxylate (5g, 16.2 mmol) indichloromethane (150 mL) at −40° C. was reacted with diisobutylaluminumhydride (1 M in dichloromethane, 36 mL, 2.2 equivalents) added dropwise.The reaction was stirred for 15 minutes after complete addition,quenched with 10% aqueous sodium potassium tartrate solution and stirredat 25° C. for 1 hour. The organic layer was separated, filtered throughcelite®(dratomaceous earth) and the filtrate was concentrated underreduced pressure. The resulting oil was purified by flash chromatographyon silica gel with a Biotage-40s column eluting with 2:98 methanol/dichloromethane to give [4-(benzylthio)-5-nitrothien-3-yl]methanol as anoil, (4.32 g, 95%). ¹H NMR (300 MHz, CDCl₃) δ ppm 4.21 (s, 2 H), 4.39(s, 2 H), 7.11 (m, 3 H), 7.23 (m, 2 H) 7.40 (s, 1 H).

[4-(benzylthio)-5-nitrothien-3-yl]methanol (3,9g, 13.9 mmol) indichloromethane (8 mL) was reacted with diisopropylethylamine (7.42 mL,3 equivalents) and methoxymethyl chloride (2.38 mL, 2.25 equivalents) at25° C. 16 hours. The reaction was concentrated under reduced pressureand the residue purified by flash chromatography on silica gel using aBiotage-40m column eluting with dichloromethane to give3-(benzylthio)-4-[(methoxymethoxy)methyl]-2-nitrothiophene as ayellowish oil, (4.32 g, 94%). ¹H NMR (300 MHz, CDCl₃) δ ppm 3.36 (s, 3H), 4.20 (s, 2 H), 4.34 (s, 2 H), 4.62 (s, 2 H), 7.13 (m, 3 H), 7.21(m,2 H), 7.40 (s, 1 H)

3-(Benzylthio)-4-[(methoxymethoxy)methyl]-2-nitrothiophene (4 g, 12.3mmol) in dichloromethane (70 mL) and 1 N aqueous hydrochloric acid (35mL) at 0° C. was reacted with chlorine gas bubbled in slowly over aperiod of 0.5 hour, then stirred for an additional 1 hour. The reactionmixture was purged with nitrogen gas to remove excess chlorine andtreated with solid sodium bisulfite (11 g) added slowly to the mixturewith stirring for 5 minutes, Dichloromethane (15 mL) and water (15 mL)were added, the organic layer was separated and eluted through 40 g of50:50 mixture of MgSO₄/Na₂SO₄). The filtrate was concentrated underreduced pressure. A solution of the concentrate (4.7 g) indichloromethane (100 mL) at −40° C. was bubbled with ammonia gas over aperiod of 10 minutes. The reaction mixture was stirred for an additional15 minutes, purged with nitrogen gas to dispel the excess ammonia andconcentrated under reduced pressure. The concentrate was purified byflash chromatography on silica gel using a Biotage-40s column elutingwith 5:95 methanol/ dichloromethane to give4-[(methoxymethoxy)methyl]-2-nitrothiophene-3-sulfonamide as an oil (2,3g, 66%). lH NMR (300 MHz, CDCl₃) δ ppm 3.31 (m, 3 H), 4,70 (s, 2 H),4.73 (s, 2 H), 7.85 (m, 2 H), 7.88 (s, 1 H).

4-[(Methoxymethoxy)methyl]-2-nitrothiophene-3-sulfonamide (1.8 g, 6.4mmol) was reacted with iron powder (1.43 g, 4 equivalents) in aceticacid (70 mL) at 50° C. for 7.5 hours then concentrated under reducedpressure A slurry of the residue in 5% methanol/dichloromethane (60mL)and water (6 mL) was filtered through silica gel (20 g) and furtherrinsed with 5% methanol/dichloromethane (300 mL). The filtrate wasconcentrated under reduced pressure and the residue purified by flashchromatography on silica gel using a Biotage-12s column eluting with2.5:97.5 methanol: dichloromethane to give 2-amino-4-[(methoxymethoxy)methyl]thiophene-3-sulfonamide (1 g, 62%). ¹H NMR(300 MHz, DMSO-d₆) δ ppm 3.30 (s, 3 H), 4.53 (s, 2 H), 4.66 (s, 2 H),6.28 (s, 1 H), 6.61 (s, 2 H), 6.94 (s, 2 H).

A solution of 3-[bis(methylthio)methylene]-1-[(cyclopropylmethyl)amino]quinoline -2,4(1 H, 3 H)-dione (500.3, 1.5 mmol) and the product of2-ami o-4-[(methoxy methoxy) methyl]thiophene-3-suifonamide (377.62 mg,15 mmol) in dioxane (15 mL) was stirred at reflux for 1.5 hours andconcentrated under reduced pressure. The residue was purified bychromatography on silica gel eluting with 0% to 10% ethylacetate/dichloromethane to give 1-[(cyclopropylmethyl)amino]-4-hydroxy-3-{7-[(methoxymethoxy)methyl]-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-3-yl}quinolin -2(1 H)-one (384.7 mg,52%). ¹H NMR (300 MHz, DMSO-d₆) δ 0.15 (m, 2 H) 0.42 (m, 2 H) 1.01 (m, 1H) 2,84 (d, J=6.99 Hz, 2 H) 4.64 (s, 2 H) 4.71 (s, 2 H) 6.36 (br s, 1 H)7.42 (m, 2 H) 7.86 (m, 1 H) 8.07 (d, J=8.46 Hz, 1 H)8.36 (m, 1 H)

To1-[(cyclopropylmethyl)amino]-4-hydroxy-3-{7-[(methoxymethoxy)methyl]-1,1-dioxido-4H -thieno[2,3-e][1,2,4]thiadiazin-3-yl}quinolin-2(1 H)-one (384.7 mg,0.78 mmol) was added a solution of hydrogen chloride in dioxane (4N, 7.8mL) at 0° C. The solution warmed to room temperature and stirred for 5.5hours and concentrated under reduced pressure. This solid was suspendedin dichloromethane (7.8 mL) and to the suspension was addedl,8-diazabicyclo[5.4.0] undec-7-ene (0.6 mL, 4.01 mmol) anddiphenylphosphoryl azide (0.85 mL, 3.94 mmol) at room temperature andstirred overnight. The solution was concentrated in vacuo. The residuewas purified by chromatography, eluting with 1%triethylamine/dichloromethane to give a triethylamine salt of3-[7-(azidomethyl)-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-1-[(cyclopropylmethyl)amino]-4-hydroxyquinolin-2(1H)-one (357 mg, 79%). MS (ESI⁻) m/z 470 (M−H)⁻. 1H NMR (300 MHz,DMSO-d₆) δ 0.22 (m, 2 H) 0.46 (br d, J=7.35 Hz, 2 H) 1.01 (m, 1 H) 4.52(s, 2 H) 5.98 (t, J=6.62 Hz, 1 H) 7.24 (s, 1 H) 7.40 (m, 1 H) 7.56 (m, 1H) 8.05 (m, 1 H).

To the solution of 3-[7-(azidomethyl)-1,1-dioxido-4H-thieno[2,3-e][l,2,4]thiadiazin-3-yl]-1-[(cyclopropylmethyl)amino]-4-hydroxyquinolin-2(1H)-one (357 mg, 0.62 mmol) in pyridine (4.6 mL) and concentratedammonium hydroxide (3 mL) was added triphenylphosphine (397 mg, 1.51mmol) at room temperature. The solution was stirred at room temperatureovernight and concentrated under reduced pressure. The residue wasdiluted with 30% hexane/toluene and the solid was filtered to give3-[7-(aminomethyl)-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-1-[(cyclopropylmethyl)amino]-4-hydroxyquinolin-2(1H)-one(250 mg, 90%). MS (ESF) m/z 446 (M+H)⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 80.21 (m, 2 H) 0.46 (br d, J=8.09 Hz, 2 H) 1.00 (m, 1 H) 4.12 (s, 2H)5.98 (t, J=6.43 Hz, 1 H) 7.12 (m, 1 H) 7.22 (s, 1 H) 7.58 (m, 1 H) 772(d, J=7.72 Hz, 1 H) 8.04 (m, 1 H).

To the suspension of the triethylamine salt of3-[7-(aminomethyl)-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-1-[(cyclopropylmethyl)amino]-4-hydroxyquinolin-2(1H)-one (85.26 mg, 0.16 mmol) in N,N-dimethylformamide (1.6 mL) was addedtriethylamine (48 □L, 0.34 mmol) and then methanesulfonyl chloride (13.3□L, 0.17 mmol) at room temperature. The solution was stirred at roomtemperature for 20 minutes and concentrated in vacuo, The residuepurified by reverse phase chromatography, eluting with 20% to 95%acetonitrile/0.1% triflouroacetic acid in water to giveN-[(3-{1-[(cyclopropylmethyl)amino]-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl}-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-7-yl)methyl]methanesulfonamide(compound II) (39.86 mg, 49%). MS (ESI⁺) m/z 524 (M+H)⁺. ¹H NMR (300MHz, DMSO-d₆) δ 0.15 (m, 2 H) 0.42 (m, 2 H) 1.01 (m, 1 H) 2.84 (d,J=7.35 Hz, 2 H) 2.99 (s, 3 H) 4.29 (d, J=6.25 Hz, 2 H) 6.37 (br s, 1 H)7.41 (m, 2 H) 7.75 (t, J=6.25 Hz, 1H) 7.87 (m, 1 H) 8.08 (d, J=8.09 Hz,1 H) 8.16 (m, 1 H) 14.46 (m, 1 H).

Example 5 Preparation ofN-{3-[1-(Cyclobutylamino)-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl]-1,1-dioxido-4H-1,2,4-benzothiadiazin-7-yl}methanesulfonamide (Compound III).

Ccompound III was prepared according to the procedure described inExample 432 of U.S. patent application Ser. No. 10/699,513, the entirecontent of which is incorporated herein by reference. The procedure isprovided below:

A solution of 1-amino-4-hydroxyquinolin-2(1 H)-one (0.516 g, 2.9 mmol)and cyclobutanone (1.05 g, 15.0 mmol) in acetic acid (0.90 g, 15.0 mmol)and methanol (20 mL) was treated portion wise with sodiumcyanoborohydride (0,94 g, 15.0 mmol), stirred for 48 hours andconcentrated. The residue was treated with 0.5 M aqueous sodiumbicarbonate, acidified to pH 2 with 1M hydrochloric acid and extractedwith ethyl acetate. The ethyl acetate was washed with brine, dried oversodium sulfate, filtered and concentrated, The crude material waschromatographed on silica gel eluting with 3:2 hexane/ethyl acetate togive 1-(cyclobutylamino)-4-hydroxyquinolin-2(1 H)-one (0.400 g, 60%). MS(ESI⁺) m/z 231 (M+H)⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 1.52 (m, 1 H) 1.63(m, 1 H) 1.96 (m, 4 H) 3.64 (m, 1 H) 5.91 (s, 1 H) 6.26 (d, J=6.62 Hz, 1H) 7.20 (t, J=8.09 Hz, 1 H) 7.61 (m, 1 H) 7.84 (m, 2 H) 11.42 (s, 1 H).

A solution of 1-(cyclobutyianiino)-4-hydroxyquinolin-2(1H)-one (0.115 g,0.5 mmol) and tris(methylthio)methyl methyl sulfate (prepared using theprocedures in SYNTHESIS, 22-25, 1988; M Barbero, S. Cadamuro, 1 Degani,R. Fochi, A. Gatti, V. Regondi) (0.27 g, 1.0 mmol) in pyridine (0316 g,4.0 mmol) and dioxane (5.0 mL) was heated at 60° C. for 30 minutes.Additional tris(methylthio)methyl methyl sulfate was added (0.27 g, 1.0mmol) and heating continued for 30 minutes. The mixture was cooled to25° C. and partitioned between ethyl acetate and water. The ethylacetate layer was washed with water, brine, dried over sodium sulfate,filtered and concentrated. The crude material was chromatographed onsilica gel eluting with 95/5 dichloromethane/ethyl acetate to give3-[bis(methylthio)methylene]-1-(cyclobutylamino)quinoline-2,4(1H,3H)-dione (0.146 g, 87% yield). MS (ESI⁺) m/z 335 (M+H)⁺. ¹H NMR (300MHz, DMSO-d₆) δ 1.54 (m, 1 H) 1.66 (m, 1 H) 1.99 (m, 4 H) 2.61 (s, 6 H)3.62 (m, 1 H) 618 (d, J=6.25 Hz, 1 H) 7.15 (t, J=7.54 Hz, 1 H) 7.63 (m,1 H) 7.72 (d, J=8.09 Hz, 1 H) 7.98 (dd, J=7.91, 1.29 Hz, 1 H).

A mixture of 2,5-diamino-benzenesulfonamide (0.288 g, 0.0015 mol, 1eq.), dichloromethane (5 mL), and pyridine (5 mL) was stirred at 0° C.Methanesulfonyl chloride (119 μL, 0.0015 mol, 1 eq.) was added dropwiseover 3 minutes. The reaction mixture was warmed to 25° and stirred for18 hours. The reaction mixture was evaporated under reduced pressure andthe residue was chromatographed on silica gel using a step gradient of0-4% methanol in dichloromethane to yield2-amino-5-[(methylsulfonyl)amino]benzenesulfonamide (68% yield). ¹H NMR(300 MHz, DMSO-d₆) δ 2.87 (s, 3H)3.39 (s, 1 H)5.80 (s, 1 H)6.78 (d,J=8.82 Hz, 1 H) 7.13 (dd, J=8.64, 2.39 Hz, 1 H) 7.29 (s, 2 H) 7.45 (d,J=2.57 Hz, 1 H) 9.21 (m, 1 H), MS (ESI⁺) m/z=266 (M+H)⁺.

A mixture of 2-amino-5-[(methylsulfonyl)amino]benzenesulfonamide (0.195g, 0.585 mmol, 1.5 eq.) and3-[bis(methylthio)methylene]-1-(cyclobutylamino)quinoline-2,4(1,3H)-dione (0.100 g, 0.390 mmol, 1.5 eq.) in anhydrous dioxane (10 mL)was heated for 1 hour at 120° C. After cooling to 25° C., the reactionmixture was treated with methanol (20 mL) and diethyl ether (20 mL) andthe precipitated product collected by vacuum filtration to yieldN-{3-[1-(cyclobutylamino)-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl]-1,1-dioxido-4H-1,2,4-benzothiadiazin-7-ylmethane sulfonamide(compound III) (25 mg, 12% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 1.69 (m,2 H) 2.13 (m, 4 H) 3.10 (s, 3 H) 3.77 (m, 1 H) 6.57 (s, 1 H) 7.44 (t,J=7.35 Hz, 1 H) 7.65 (m, 3 H) 7.89 (t, J=7.35 Hz, 1 H) 8.06 (d, J=8.46Hz, 1 H) 8.16 (d, J=7.72 Hz, 1 H) 10.31 (s, 1 H) 14.16 (s, 1 H) 15.03(s, 1 H). MS (ESI⁺) m/z=504 (M+H)⁺.

Example 6 Comparison of Pharmacokinetic Profiles of Compounds I, II, andIII

Compounds I, II and III were prepared as a solution in a DMSO: PEG-400vehicle at a concentration of 5 mg/mL shortly before oral dosing.

Male Sprague-Dawley derived rats, weighing 250-350 grams, were obtainedfrom Charles River Laboratories, Inc. (Wilmington, Mass.). The animalswere fasted overnight prior to dosing and throughout the study period,but were allowed water ad libitum. Animals were allowed chow ad libitumpost 12 hr.

Each study used a group of 3 rats. Each rat received a 5 mg/kg (1 mL/kg)oral dose of compound I, II or III administered by gavage. At selectedtime points after dosing, groups of three rats were euthanized with CO₂and exsanguinated by cardiac puncture. The entire liver tissue from eachanimal was removed and placed in a labeled plastic container. Groups ofrats were sacrificed 1, 12 and 24 hours after drug administration. Theliver samples were stored on ice (about 4° C.), and then assayed for theconcentration of each compound using high performance liquidchromatographic procedures,

FIG. 1 and Table 1 show that 24 hours after oral dosing, the liverconcentration of

compound I is about 8-20 times higher than those of compounds II andIII.

TABLE 1 Liver Concentrations of Compounds after a 5 mg/kg Oral Dose inRats Liver Concentration after Oral Dosing (μg/g) compound 1 hour 12hours 24 hours I 18.72 19.16 2.42 II 18.92 7.92 0.12 III 8.79 4.14 0.28

The 50% inhibitory concentration (EC₅₀) of compound I, when tested usingHCV replicon assays, is about 2,5 nM. Therefore, the concentration ofcompound I in liver 24 hours after oral dosing is more than 1,800-foldhigher than the compound's EC₅₀ value. In contrast, the EC₅₀ multiplesof compounds II and III (i.e., the ratios of the post 24-hour liverconcentrations of compound II or III over their respective EC₅₀ values)are significantly lower than that of compound I.

Example 7 Antiviral Activity of Combination of Compound I with VX-950

The effect of compound I on HCV replicon was evaluated alone or incombination with other anti-HCV agents. HCV Ib—N replicon cells werepassaged in the presence of compound I, compound VX-950, interferonalpha (IFN), or combinations thereof, but in the absence of neomycin. Inuntreated control cells, the HCV RNA level was relatively stable over 2months passage. Although the HCV RNA levels significantly reduced duringtreatment with any of the individual compounds or agents atconcentrations 10 to 20-fold above their respective EC₅₀, none of themeliminated the HCV RNA from the replicon cells The EC₅₀ values representthe 50% inhibitory concentrations of these compounds/agents in repliconcell assays.

The combination of IFN with either compound I or VX-950 appearedadditive, but neither combination completely eliminated HCV RNA fromreplicon cells. However, the mechanisms of action of IFN in thetreatment of HCV in vivo are complicated and may involve both direct andindirect antiviral effects, the latter of which is not assessed in thereplicon cell assay.

In marked contrast, the combination of compounds I and VX-950 atconcentrations 10 times above each respective EC₅₀ successfully reducedHCV RNA to undetectable levels. After passage 6, cells treated with thiscombination were treated with neomycin to select any colonies withreplication of the replicon sufficient to confer the neomycin-resistantphenotype to the host cell. No colonies were observed, suggestingcomplete elimination of HCV replicon RNA from the cells.

To further assess the antiviral effect of the combination of compound Iwith other HCV inhibitors, each compound/agent alone and combinationsfrom 4-fold to 1/8 of EC₅₀ were tested for inhibition of HCV using acheckerboard titration pattern (two-fold serial dilutions). Synergy,additivity and antagonism were evaluated using the Bliss independencemodel. Synergistic antiviral effect was observed at low concentrationsof compounds I and VX-950. Additivity was observed at higherconcentrations of either compound. The combination of I with IFN wasadditive at the majority of the concentrations and synergistic at lowconcentration combinations. These results suggest that a combination ofI with another an-HCV compound acting on a different target in vivo canresult in significantly enhanced antiviral activity.

The foregoing description of the present invention provides illustrationand description, but is not intended to be exhaustive or to limit theinvention to the precise one disclosed. Modifications and variations arepossible in light of the above teachings or may be acquired frompractice of the invention. Thus, it is noted that the scope of theinvention is defined by the claims and their equivalents.

1. A compound of formula (I),

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof,wherein: A is a monocyclic or bicyclic ring selected from the groupconsisting of aryl, cycloalkyl, cycloalkenyl, heteroaryl andheterocycle; R¹ is cyclobutyl-N(R_(a))—, wherein R¹ is optionallysubstituted with at least 1, 2 or 3 substituents each of which isindependently selected from the group consisting of alkyl, alkenyl,alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloaikoxy, aryl,heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl)(OR_(c)), -(alkyl)(NR_(c)R_(c)), —SR_(c), —S(O)R_(c),—S(O)₂R_(c), —OR_(c), —N(R_(c))(R_(c)), —C(O)R_(c), —C(O)OR_(c) and—C(O)NR_(c)R_(c); R² and R³ are each independently selected from thegroup consisting of hydrogen, alkenyl, alkynyl, alkoxyalkyl,alkoxycarbonyl, alkyl, aryl, arylalkyl, heteroaryl, heterocycle,heteroarylalkyl, cyano, halo, —N(R_(a))(R_(b)), R_(a)R_(b)NC(O)—,—SR_(a), —S(O)R_(a), —SO₂R_(a) and R_(a)C(O)—; wherein R² and R³ areeach independently optionally substituted with at least 1, 2 or 3substituents each of which is independently selected from the groupconsisting of R_(a), alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro,haloalkyl, -(alkyl)(OR_(k)), -alkyl)(NR_(a)R_(b)), —SR_(a), —S(O)R_(a),—S(O)₂R_(a), —OR_(k), —N(R_(a))(R_(b)), —C(O)R_(a), —C(O)OR_(a) and—C(O)NR_(a)R_(b); alternatively, R² and R³, together with the carbonatoms to which they are attached, form a five- or six-membered ringselected from the group consisting of aryl, cycloalkyl, heteroaryl andheterocycle, wherein said five- or six-membered ring is optionallysubstituted with (R⁶)m; R⁴ is selected from the group consisting ofalkoxy, arylalkoxy, aryloxy, halo, hydroxy, R_(a)R_(b)N—, N₃- andR_(c)S—, wherein R⁴ is optionally substituted with at least 1 or 2substituents each of which is independently selected from the groupconsisting of halo, nitro, cyano, —OH, —NH₂, and —COOH; R⁵ isindependently selected at each occurrence from the group consisting ofalkenyl, alkoxy, alkyl, alkynyl, aryl, arylalkyl, arylcarbonyl, aryloxy,azidoalkyl, formyl, halo, haloalkyl, halocarbonyl, heteroaryl,heteroarylalkyl, heterocycle, heterocyclealkyi, hydoxyalkyl, cycloalkyl,cyano, cyanoalkyl, nitro, R_(a)R_(b)N—, R_(a)C(O)—, R_(a)S—,R_(a)(O)₂S—, R_(a)(O)₂S—, R_(a)R_(b)Nalkyl-, R_(a)(O)SN(R_(f))—,R_(a)SO₂N(R_(f))—, R_(a)(O)SN(R_(f))alkyl-,R_(a)SO₂N(R_(f))alkyl-R_(a)R_(b)NSO₂N(R_(f))—,R_(a)R_(b)NSO₂N(R_(f))alkyl-, R_(a)R_(b)NC(O)—, R_(k)OC(O)—,R_(k)OC(O)alkyl-, R_(k)Oalkyl-, R_(a)R_(b)NSO₂—, R_(a)R_(b)NSO₂alkyl-,(R_(b)O)(R_(a))P(O)O—- and —OR_(k), wherein each R⁵ is independentlyoptionally substituted at each occurrence with at least 1, 2 or 3substituents each of which is independently selected from the groupconsisting of alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro,haloalkyl, haloaikoxy, aryl, heteroaryl, heterocycle, arylalkyl,heteroarylalkyl, alkoxyalkoxyalkyl, -(alkyl)(OR_(c)),-(alkyl)(NR_(c)R_(d)), —SR_(c), —S(O)R_(c), —S(O)₂R_(c), —OR_(c),—N(R_(c)) (R_(d)), —C(O)R_(c), —C(O)OR_(c) and —C(O)NR_(c)R_(d); R⁶ isindependently selected at each occurrence from the group consisting ofalkyl, alkenyl, alkynyl, halo, cyano, nitro, haloalkyl, haloaikoxy,aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl,heterocyclealkyl, -(alkyl)(OR_(k)), -(alkyl)(NR_(a)R_(b)), —SR_(a),—S(O)R_(a), —S(O)₂R_(a), —OR_(k), —N(R_(a))(R_(b)), —C(O)R_(a);—C(O)OR_(a) and —C(O)NR_(a)R_(b); wherein each R⁶ is independentlyoptionally substituted at each occurrence with at least 1, 2 or 3substituents each of which is independently selected from the groupconsisting of alkyl, alkenyl, alkynyl, oxo, halo, haloalkyl, cyano,nitro, -OR_(a), —NR_(a)R_(b), —SR_(a), —SOR_(a), —SO₂R_(a), —C(O)OR_(a),—C(O)NR_(a)R_(b) and —NC(O)R_(a); R_(a) and R_(b) are each independentlyselected at each occurrence from the group consisting of hydrogen,alkenyl, alkyl, aikylsulfanylalkyl, aryl, arylalkenyl, arylalkyl,cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl,cycioalkylalkyl, cycloalkylalkenyl, formylalkyl, haloalkyl, heteroaryl,heteroarylalkenyl, heteroarylalkyl, heterocycle, heterocyclealkenyl,heterocyclealkyi, hydroxyalkylcarbonyl, nitroalkyl, R_(c)R_(d)N—,R_(p)O-, R_(p)Oalkyl-, R_(c)R_(d)Nalkyl-, R_(c)R_(d)NC(O)alkyl-,R_(c)SO₂—, R_(c)SO₂alkyl-, R_(c)C(O)—, R_(c)C(O)alkyl-, R_(c)OC(O)—,R_(c)OC(O)alkyl-, R_(c)R_(d)NalkylC(O)—, R_(c)R_(d)NC(O)—,R_(c)R_(d)NC(O)Oalkyl-, and R_(c)R_(d)NC(O)N(R_(c)) alkyl-, whereinR_(a) and R_(b) are each independently optionally substituted at eachoccurrence with at least 1 or 2 substituents each of which isindependently selected from the group consisting of alkyl, alkenyl,alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl,heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl)(OR_(c)), -(alkyl)(NR_(c)R_(d)), —SR_(c), —S(O)R_(c),—S(O)₂R_(c), —OR_(c), —N(R_(c))(R_(d)), —C(O)R_(c), —C(O)OR_(c) and—C(O)NR_(c)R_(d); alternatively, R_(a) and R_(b), together with thenitrogen atom to which they are attached, form a three- to six-memberedring selected from the group consisting of heteroaryl and heterocycle,wherein the heteroaryl and heterocycle are each independently optionallysubstituted at each occurrence with at least 1, 2 or 3 substituents eachof which is independently selected from the group consisting of alkyl,alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl,heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl)(OR_(c)), -(alkyl)(NR_(c)R_(d)), -alkylSO₂NR_(c)R_(d),-alkylC(O)NR_(c)R_(d), —SR_(c), —S(O)R_(c), —S(O)₂R_(c), —OR_(c),—N(R_(c))(R_(d)), —C(O)R_(c), —C(O)OR_(c) and —C(O)NR_(c)R_(d); R_(c)and R_(d) are each independently selected at each occurrence from thegroup consisting of hydrogen, —NR_(f)R_(h), —OR_(f), —CO(R_(f)),—SR_(f), —SOR_(f), —SO₂R_(f), —C(O)NR_(f)R_(b), —SO₂NR_(f)R_(h),—C(O)OR_(f), alkenyl, alkyl, alkynyl, cycloalkyl, cycloalkylalkyi,cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, haloalkyl, heteroaryl,heteroarylalkyl, heterocycle and heterocyclealkyl; wherein each R_(c)and R_(d) is independently optionally substituted at each occurrencewith at least 1, 2, or 3 substituents each of which is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl, oxo,halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl,heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl)(OR_(f)), -(alkyl)(NR_(f)R_(h)), —SR_(f), —S(O)R_(f),—S(O)₂R_(f), —OR_(f), —N(R_(f))(R_(h), —C(O)R_(f), —C(O)OR_(f),—C)O)NR_(f)R_(h), —C(O)N(H)NR_(f)R_(h), —N(R_(c))C(O)OR_(f),—N(R_(c))SO₂NR_(f)R_(h), —N(R_(c))C(O)NR₁R_(b),-alkylN(R_(c))C(O)OR_(f), -alkylN(Rhd c)SO₂NR_(f)R_(k), and-alkylN(R_(c))C(O)NR_(f)R_(h); alternatively, R_(c) and R_(d), togetherwith the nitrogen atom to which they are attached, form a three- tosix-membered ring selected from the group consisting of heteroaryl andheterocycle, wherein the heteroaryl and heterocycle are eachindependently optionally substituted at each occurrence with at least 1,2 or 3 substituents each of which is independently selected from thegroup consisting of alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro,haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl,heteroarylalkyl, alkoxyalkoxyalkyl, -(alkyl)(OR_(f)),-(alkyl)(NR_(f)R_(h)), —SR_(f), —S(O)R_(f), —S(O)₂R_(f), —OR_(f),—N(R_(f))(R_(h)), —C(O)R_(f), —C(O)OR_(f) and —C(O)NR_(f)R_(h); R_(c) isindependently selected at each occurrence from the group consisting ofhydrogen, alkenyl, alkyl and cycloalkyl; R_(f) and R_(h) are eachindependently selected at each occurrence from the group consisting ofhydrogen, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyi,cycloalkenyl, cycloalkenylalkyl, heterocycle, heterocyclealkyl,heteroaryi and heteroarylalkyl; wherein each R_(f) and R_(h) isindependentiy optionally substituted at each occurrence with at least 1,2 or 3 substituents each of which is independently selected from thegroup consisting of alkyl, alkenyl, alkynyl, cyano, halo, oxo, nitro,aryl, arylalkyl, cycloalkyl, cycloalkenyl, heterocycle, heteroaryl,heteroarylalkyl, —OH, —O(alkyl), —NH₂, —N(H)(alkyl), —N(alkyl)₂,—S(alkyl), —S(O)(alkyl), —SO₂alkyl, -alkyl-OH, -alkyl-O-alkyl,-alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂, -alkylS(alkyl),-alkylS(O)(alkyl), -alkylSO₂alkyl, —N(H)C(O)NH₂, —C(O)OH, —C(O)O(alkyl),—C(O)alkyl, —C(O)NH₂, —C(O)NH₂, —C(O)N(H)(alkyl), and —C(O)N(alkyl)₂;alternatively, R( and Rlt, together with the nitrogen atom to which theyare attached, form a three- to seven-membered ring selected from thegroup consisting of heterocycle and heteroaryl; wherein the heterocycleand heteroaryl are each independently optionally substituted at eachoccurrence with at least 1, 2 or 3 substituents each of which isindependently selected from the group consisting of alkyl, alkenyl,alkynyl, cyano, halo, oxo, nitro, aryl, arylalkyl, cycloalkyl,cycloalkenyl, heterocycle, heteroaryl, heteroarylalkyl, —OH, —O(alkyl),—NH₂, —N(H)(alkyl), —N(alkyl)₂, —S(alkyl), —S(alkyl), —S(O)(alkyl),-alkyl-OH, -alkyl-O-alkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylS(alkyl),-alkylS(O)(alkyl), -alkylSO₂alkyl, -alkylN(alkyl)₂, —N(H)C(O)NH₂,—C(O)OH, —C(O)O(alkyl), —C(O)alkyl, —C(O)NH₂, —C(O)NH₂,—C(O)N(H)(alkyl), and —C(O)N(alkyl)₂; R_(k) is independently selected ateach occurrence from the group consisting of hydrogen, alkenyl, alkyl,aryl, arylalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl,cycloalkyl, cycloalkylalkyl, formylalkyl, haloalkyl, heteroaryl,heteroarylalkyl, heterocycle, heterocyclealkyl, nitroalkyl,R_(a)R_(b)Nalkyl-, R_(a)Oalkyl-, R_(a)R_(b)NC(O)—, R_(a)R_(b)NC(O)alkyl,R_(a)S—, R_(a)S(O)—, R_(a)SO₂, R_(a)Salkyl-, Ra(O)Salkyl-,R_(a)SO₂alkyl-, R_(a)OC(O)—, R_(a)OC(O)alkyl-, R_(a)C(O)— andR_(a)C(O)alkyl-, wherein each R_(k) is independently optionallysubstituted at each occurrence with at least 1, 2, or 3 substituentseach of which is independently selected from the group consisting ofalkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy,aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl,alkoxyalkoxyalkyl, -(alkyl)(OR_(c)), -(alkyl)(NR_(c)R_(d)), —SR_(c),—S(O)R_(c), —S(O)₂R_(c), —OR_(c), —N(R_(c))(R_(d)), —C(O)R_(c),—C(O)OR_(c) and —C(O)NR_(c)R_(d); R_(p) is independently selected ateach occurrence from the group consisting of hydrogen, alkenyl, alkyl,aryl, arylalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl,cycloalkyl, cycloalkylalkyl, formylalkyl, haloalkyl, heteroaryl,heteroarylalkyl, heterocycle, heterocyclealkyl, and nitroalkyl, whereineach R_(p) is independently optionally substituted at each occurrencewith at least 1,2, or 3 substituents each of which is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl, oxo,halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl,heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl)(OR_(c)), -(alkyl)(NR_(c)R_(d)), —SR_(c), —S(O)R_(c),—S(O)₂R_(c), —OR_(c), —N(R_(c))(R_(d)), —C(O)R_(c), —C(O)OR_(c) and—C(O)NR_(c)R_(d); m is 1, 2, 3, or 4; n is 1, 2, 3, or 4; and wherein atleast one R⁵ is R_(a)SO₂N(R_(f))alkyl-.
 2. The compound of claim 1, or apharmaceutically acceptable salt, stereoisomer or tautomer thereof,wherein A is heteroaryl, and R² and R³ together with the carbon atoms towhich said R² and R³ are attached form a five- or six-membered ringselected from the group consisting of phenyl, pyridyl, pyrimidinyl,pyridazinyl, thienyl, furanyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl,imidazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl,tetrazolyi, cyclopentyl and cyclohexyl.
 3. The compound of claim 1, or apharmaceutically acceptable salt, stereoisomer or tautomer thereof,wherein A is pyridyl, phenyl, thienyl, imidazolyl, benzimidazolyl,benzoxazolyl or benzoxazinyl, and R² and R³ together with the carbonatoms to which said R² and R³ are attached form a five- or six-memberedring selected from the group consisting of phenyl, pyridyl, thienyl,pyrimidinyl, pyrazolyl, pyridazinyl, cyclohexyl and cyclopentyl, andwherein R⁴ is hydroxy.
 4. The compound of claim 1, or a pharmaceuticallyacceptable salt, stereoisomer or tautomer thereof, wherein A is pyridyl,phenyl, thienyl, imidazolyl, benzimidazolyl, benzoxazolyl orbenzoxazinyl, and R² and R³ together with the carbon atoms to which saidR²and R³ are attached form a five- or six-membered ring selected fromthe group consisting of phenyl, pyridyl, thienyl, pyrimidinyl,pyrazolyl, pyridazinyl, cyclohexyl and cyclopentyl, wherein R⁴ ishydroxy, R¹ is cyclobutyl-N(H)—, n is 1, and R⁵ is R_(a)SO₂N(H)-R_(j),and wherein R_(j) is —CH₂- or C₂-C₄alkylene.
 5. The compound of claim 4,or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof,wherein A is phenyl, and R² and R³ together with the carbon atoms towhich said R² and R³ are attached form pyridyl.
 6. The compound of claim4, or a pharmaceutically acceptable salt, stereoisomer or tautomerthereof, wherein A is phenyl, and R² and R³ together with the carbonatoms to which said R² and R³ are attached form thienyl.
 7. The compoundof claim 4, or a pharmaceutically acceptable salt, stereoisomer ortautomer thereof, wherein A is phenyl, and R² and R³ together with thecarbon atoms to which said R² and R³ are attached form is phenyl.
 8. Thecompound of claim 4, or a pharmaceutically acceptable salt, stereoisomeror tautomer thereof, wherein A is thienyl, and R² and R³ together withthe carbon atoms to which said R² and R³ are attached form phenyl
 9. Thecompound of claim 4, or a pharmaceutically acceptable salt, stereoisomeror tautomer thereof, wherein A is

and R² and R³ together with the carbon atoms to which said R² and R³ areattached form phenyl
 10. The compound of claim 4, or a pharmaceuticallyacceptable salt, stereoisomer or tautomer thereof, wherein A is

and R² and R³ together with the carbon atoms to which said R² and R³ areattached form phenyl
 11. The compound of claim 4, or a pharmaceuticallyacceptable salt, stereoisomer or tautomer thereof, wherein A is pyridyl,and R² and R³ together with the carbon atoms to which said R² and R³ areattached form phenyl.
 12. The compound of claim 4, or a pharmaceuticallyacceptable salt, stereoisomer or tautomer thereof, wherein R⁵ isCH₃SO₂N(H)—CH₂—.
 13. The compound of claim 1, or a pharmaceuticallyacceptable salt, stereoisomer or tautomer thereof, wherein the compoundisN-[(3-{1-[(cyclobutyl)amino]-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-yl}-1,1-dioxo-1,4-dihydro-1λ⁶-thieno[2,3-e][1,2,4]thiadiazin-7-yl)methyl]methanesulfonamide
 14. The compound of claim 13, or a pharmaceuticallyacceptable salt, stereoisomer or tautomer thereof, that is substantiallypure.
 15. A pharmaceutical composition comprising a compound, salt,stereoisomer or tautomer according to claim 1, and a pharmaceuticallyacceptable carrier.
 16. The pharmaceutical composition of claim 15,further comprising another therapeutic agent.
 17. The pharmaceuticalcomposition of claim 15, further comprising another anti-HCV agent. 18.A method for treating or preventing HCV infection, comprisingadministering an effective amount of a compound, salt, stereoisomer ortautomer according to claim 1, to a patient in need thereof, therebytreating or preventing HCV infection in said patient.
 19. A process forpreparation of the compound of claim 1, comprising: (a) contacting acompound of formula (26)

with a reagent selected from the group consisting of (1) carbondisulfide and a methylating agent, (2) tris(methylthio)methyl methylsulfate, and (3) tris(methylthio)methyl methyl tetrafluoroborate, in thepresence of a base, to provide a compound of formula (27)

(b) contacting the compound of formula (27) with a compound of formula(13)


20. The process of claim 19, wherein the compound of formula (13) is2-amino-4-(methanesulfonylamino-methyl)-thiophene-3-sulfonic acid amide:


21. A process for preparing a compound of formula (13A):

comprising: (a) reacting compound of formula (A) with an agent selectedfrom the group consisting of (1) isopropyl magnesium chloride, (2)isopropyl magnesium bromide, and (3) magnesium metal to obtain acompound of formula (B) in which X is selected from the group consistingof chloro and bromo:

(b) reacting the compound of formula (B) with 4-methylbenzenesulfonylcyanide or ClC(O)O-alkyl to obtain a compound of formula (C) in which Eis CN or C(O)O-alkyl: